Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer
Abstract
:Simple Summary
Abstract
1. Parallels between Aberrant Hormone Receptor Signalling in Breast and Prostate Cancer
2. Dysregulation of Translation Is a Common Feature of Cancer
2.1. Translation Initiation
2.2. Translation Elongation
2.3. Integrated Stress Response (ISR)
3. Genomic Alterations to Translation Factors in Breast and Prostate Cancer
4. Interplay between mRNA Translation and ER Signalling
4.1. ER Selectively Controls Translation Initiation
4.2. mTORC1 Directly Controls ER-Mediated Transcription
4.3. ER Is an Important Player in the UPR
5. New Roles for AR Signalling in mRNA Translation
5.1. AR Indirectly Regulates Translation Initiation
5.2. AR and UPR
6. Targeting Pathways That Regulate mRNA Translation in BC and PC
6.1. Targeting Pathways That Regulate mRNA Translation
6.1.1. PI3K
6.1.2. MNK
6.1.3. eIF4E
6.1.4. eIF4A
6.2. Targeting Ribosome Biogenesis
6.3. Targeting the UPR
7. Drawbacks and New Hopes in Treatments Targeting mTOR in BC and PC
7.1. Rationale for Application of mTORis as an Anti-BC/PC Treatment
7.2. Early Trials Using Rapalogs in BC/PC
7.3. The Future of mTOR Inhibition as a Therapy for Breast and Prostate Cancer
8. Conclusions, Future Perspectives and Outstanding Questions
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- How is translation modulated during adaption to anti-estrogen/androgen therapies and in response to direct alterations to AR/ER (e.g., mutations and truncations)?
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- Why do different ER/AR ligands exert distinct downstream effects on protein synthesis?
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- How do cancer cells balance the need for increased protein synthesis while avoiding UPR?
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- Will single-cell technologies address key mechanistic questions related to the interplay between AR/ER signalling and protein synthesis?
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- Does the cytotoxicity of drugs that target the translation modulators (e.g., mTORis) primarily rely on their effect on protein synthesis?
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- How do we identify BC/PC patients who are likely to benefit from protein synthesis-targeted therapies? Can we use translation-related genetic profiles to tailor personalized treatment regimens? For example, patients harbouring PTEN/PI3K/mTOR mutations would be expected to gain the most benefit from PI3K/mTOR inhibitors.
Funding
Acknowledgments
Conflicts of Interest
References
- Risbridger, G.P.; Davis, I.D.; Birrell, S.N.; Tilley, W.D. Breast and prostate cancer: More similar than different. Nat. Rev. Cancer 2010, 10, 205–212. [Google Scholar] [CrossRef] [PubMed]
- Manavathi, B.; Samanthapudi, V.S.; Gajulapalli, V.N. Estrogen receptor coregulators and pioneer factors: The orchestrators of mammary gland cell fate and development. Front. Cell Dev. Biol. 2014, 2, 34. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Obinata, D.; Takayama, K.; Takahashi, S.; Inoue, S. Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer. Cancers 2017, 9, 22. [Google Scholar] [CrossRef] [Green Version]
- Karamouzis, M.V.; Papavassiliou, K.A.; Adamopoulos, C.; Papavassiliou, A.G. Targeting Androgen/Estrogen Receptors Crosstalk in Cancer. Trends Cancer 2016, 2, 35–48. [Google Scholar] [CrossRef]
- Pomerantz, M.M.; Qiu, X.; Zhu, Y.; Takeda, D.Y.; Pan, W.; Baca, S.C.; Gusev, A.; Korthauer, K.D.; Severson, T.M.; Ha, G.; et al. Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nat. Genet. 2020, 52, 790–799. [Google Scholar] [CrossRef]
- Kovacs, T.; Szabo-Meleg, E.; Abraham, I.M. Estradiol-Induced Epigenetically Mediated Mechanisms and Regulation of Gene Expression. Int. J. Mol. Sci. 2020, 21, 3177. [Google Scholar] [CrossRef]
- Coutinho, I.; Day, T.K.; Tilley, W.D.; Selth, L.A. Androgen receptor signaling in castration-resistant prostate cancer: A lesson in persistence. Endocr. Relat. Cancer 2016, 23, T179–T197. [Google Scholar] [CrossRef]
- Belachew, E.B.; Sewasew, D.T. Molecular Mechanisms of Endocrine Resistance in Estrogen-Positive Breast Cancer. Front. Endocrinol. 2021, 12, 599586. [Google Scholar] [CrossRef]
- Dobrzycka, K.M.; Townson, S.M.; Jiang, S.; Oesterreich, S. Estrogen receptor corepressors—A role in human breast cancer? Endocr. Relat. Cancer 2003, 10, 517–536. [Google Scholar] [CrossRef] [Green Version]
- Baniahmad, A. Nuclear hormone receptor co-repressors. J. Steroid Biochem. Mol. Biol. 2005, 93, 89–97. [Google Scholar] [CrossRef]
- Groner, A.C.; Brown, M. Role of steroid receptor and coregulator mutations in hormone-dependent cancers. J. Clin. Investig. 2017, 127, 1126–1135. [Google Scholar] [CrossRef] [Green Version]
- Schuller, A.P.; Green, R. Roadblocks and resolutions in eukaryotic translation. Nat. Rev. Mol. Cell Biol. 2018, 19, 526–541. [Google Scholar] [CrossRef]
- Kong, J.; Lasko, P. Translational control in cellular and developmental processes. Nat. Rev. Genet. 2012, 13, 383–394. [Google Scholar] [CrossRef]
- Truitt, M.L.; Ruggero, D. New frontiers in translational control of the cancer genome. Nat. Rev. Cancer 2016, 16, 288–304. [Google Scholar] [CrossRef] [Green Version]
- Tahmasebi, S.; Khoutorsky, A.; Mathews, M.B.; Sonenberg, N. Translation deregulation in human disease. Nat. Rev. Mol. Cell Biol. 2018, 19, 791–807. [Google Scholar] [CrossRef]
- Potter, C.J.; Pedraza, L.G.; Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 2002, 4, 658–665. [Google Scholar] [CrossRef]
- Manning, B.D.; Tee, A.R.; Logsdon, M.N.; Blenis, J.; Cantley, L.C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 2002, 10, 151–162. [Google Scholar] [CrossRef]
- Inoki, K.; Li, Y.; Zhu, T.; Wu, J.; Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 2002, 4, 648–657. [Google Scholar] [CrossRef]
- Ma, L.; Chen, Z.; Erdjument-Bromage, H.; Tempst, P.; Pandolfi, P.P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005, 121, 179–193. [Google Scholar] [CrossRef] [Green Version]
- Roux, P.P.; Ballif, B.A.; Anjum, R.; Gygi, S.P.; Blenis, J. Tumor-Promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. USA 2004, 101, 13489–13494. [Google Scholar] [CrossRef] [Green Version]
- Liu, G.Y.; Sabatini, D.M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 2020, 21, 183–203. [Google Scholar] [CrossRef] [PubMed]
- Mossmann, D.; Park, S.; Hall, M.N. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat. Rev. Cancer 2018, 18, 744–757. [Google Scholar] [CrossRef] [PubMed]
- Bhat, M.; Robichaud, N.; Hulea, L.; Sonenberg, N.; Pelletier, J.; Topisirovic, I. Targeting the translation machinery in cancer. Nat. Rev. Drug Discov. 2015, 14, 261–278. [Google Scholar] [CrossRef] [PubMed]
- Chung, J.; Kuo, C.J.; Crabtree, G.R.; Blenis, J. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 1992, 69, 1227–1236. [Google Scholar] [CrossRef]
- Pause, A.; Belsham, G.J.; Gingras, A.C.; Donze, O.; Lin, T.A.; Lawrence, J.C., Jr.; Sonenberg, N. Insulin-Dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 1994, 371, 762–767. [Google Scholar] [CrossRef]
- Pelletier, J.; Sonenberg, N. The Organizing Principles of Eukaryotic Ribosome Recruitment. Annu. Rev. Biochem. 2019, 88, 307–335. [Google Scholar] [CrossRef]
- Ueda, T.; Watanabe-Fukunaga, R.; Fukuyama, H.; Nagata, S.; Fukunaga, R. Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Mol. Cell Biol. 2004, 24, 6539–6549. [Google Scholar] [CrossRef] [Green Version]
- Roux, P.P.; Topisirovic, I. Signaling Pathways Involved in the Regulation of mRNA Translation. Mol. Cell Biol. 2018, 38. [Google Scholar] [CrossRef] [Green Version]
- Zindy, P.; Berge, Y.; Allal, B.; Filleron, T.; Pierredon, S.; Cammas, A.; Beck, S.; Mhamdi, L.; Fan, L.; Favre, G.; et al. Formation of the eIF4F translation-initiation complex determines sensitivity to anticancer drugs targeting the EGFR and HER2 receptors. Cancer Res. 2011, 71, 4068–4073. [Google Scholar] [CrossRef] [Green Version]
- Liu, Y.; Horn, J.L.; Banda, K.; Goodman, A.Z.; Lim, Y.; Jana, S.; Arora, S.; Germanos, A.A.; Wen, L.; Hardin, W.R.; et al. The androgen receptor regulates a druggable translational regulon in advanced prostate cancer. Sci. Transl. Med. 2019, 11. [Google Scholar] [CrossRef]
- Knight, J.R.P.; Garland, G.; Poyry, T.; Mead, E.; Vlahov, N.; Sfakianos, A.; Grosso, S.; De-Lima-Hedayioglu, F.; Mallucci, G.R.; von der Haar, T.; et al. Control of translation elongation in health and disease. Dis. Model. Mech. 2020, 13. [Google Scholar] [CrossRef] [Green Version]
- Proud, C.G. Regulation and roles of elongation factor 2 kinase. Biochem. Soc. Trans. 2015, 43, 328–332. [Google Scholar] [CrossRef]
- Carlberg, U.; Nilsson, A.; Nygard, O. Functional properties of phosphorylated elongation factor 2. Eur. J. Biochem. 1990, 191, 639–645. [Google Scholar] [CrossRef]
- Ryazanov, A.G.; Shestakova, E.A.; Natapov, P.G. Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation. Nature 1988, 334, 170–173. [Google Scholar] [CrossRef]
- Ryazanov, A.G.; Natapov, P.G.; Shestakova, E.A.; Severin, F.F.; Spirin, A.S. Phosphorylation of the elongation factor 2: The fifth Ca2+/calmodulin-dependent system of protein phosphorylation. Biochimie 1988, 70, 619–626. [Google Scholar] [CrossRef]
- Moazed, D.; Noller, H.F. Intermediate states in the movement of transfer RNA in the ribosome. Nature 1989, 342, 142–148. [Google Scholar] [CrossRef]
- Wang, X.; Regufe da Mota, S.; Liu, R.; Moore, C.E.; Xie, J.; Lanucara, F.; Agarwala, U.; Pyr Dit Ruys, S.; Vertommen, D.; Rider, M.H.; et al. Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling. Mol. Cell Biol. 2014, 34, 4088–4103. [Google Scholar] [CrossRef] [Green Version]
- Wang, X.; Li, W.; Williams, M.; Terada, N.; Alessi, D.R.; Proud, C.G. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 2001, 20, 4370–4379. [Google Scholar] [CrossRef]
- Horman, S.; Beauloye, C.; Vertommen, D.; Vanoverschelde, J.L.; Hue, L.; Rider, M.H. Myocardial ischemia and increased heart work modulate the phosphorylation state of eukaryotic elongation factor-2. J. Biol. Chem. 2003, 278, 41970–41976. [Google Scholar] [CrossRef] [Green Version]
- Hetz, C.; Zhang, K.; Kaufman, R.J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 2020, 21, 421–438. [Google Scholar] [CrossRef]
- Wang, M.; Kaufman, R.J. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer 2014, 14, 581–597. [Google Scholar] [CrossRef]
- Harding, H.P.; Zhang, Y.; Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999, 397, 271–274. [Google Scholar] [CrossRef] [PubMed]
- Dever, T.E.; Feng, L.; Wek, R.C.; Cigan, A.M.; Donahue, T.F.; Hinnebusch, A.G. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell 1992, 68, 585–596. [Google Scholar] [CrossRef]
- Ranu, R.S.; London, I.M. Regulation of protein synthesis in rabbit reticulocyte lysates: Additional initiation factor required for formation of ternary complex (eIF-2.GTP.Met-tRNAf) and demonstration of inhibitory effect of heme-regulated protein kinase. Proc. Natl. Acad. Sci. USA 1979, 76, 1079–1083. [Google Scholar] [CrossRef] [Green Version]
- Meurs, E.F.; Watanabe, Y.; Kadereit, S.; Barber, G.N.; Katze, M.G.; Chong, K.; Williams, B.R.; Hovanessian, A.G. Constitutive expression of human double-stranded RNA-activated p68 kinase in murine cells mediates phosphorylation of eukaryotic initiation factor 2 and partial resistance to encephalomyocarditis virus growth. J. Virol. 1992, 66, 5805–5814. [Google Scholar] [CrossRef] [Green Version]
- Pakos-Zebrucka, K.; Koryga, I.; Mnich, K.; Ljujic, M.; Samali, A.; Gorman, A.M. The integrated stress response. EMBO Rep. 2016, 17, 1374–1395. [Google Scholar] [CrossRef] [Green Version]
- Hetz, C. The unfolded protein response: Controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol. 2012, 13, 89–102. [Google Scholar] [CrossRef]
- Costa-Mattioli, M.; Walter, P. The integrated stress response: From mechanism to disease. Science 2020, 368. [Google Scholar] [CrossRef]
- Martincorena, I.; Raine, K.M.; Gerstung, M.; Dawson, K.J.; Haase, K.; Van Loo, P.; Davies, H.; Stratton, M.R.; Campbell, P.J. Universal Patterns of Selection in Cancer and Somatic Tissues. Cell 2017, 171, 1029–1041.e21. [Google Scholar] [CrossRef]
- Bailey, M.H.; Tokheim, C.; Porta-Pardo, E.; Sengupta, S.; Bertrand, D.; Weerasinghe, A.; Colaprico, A.; Wendl, M.C.; Kim, J.; Reardon, B.; et al. Comprehensive Characterization of Cancer Driver Genes and Mutations. Cell 2018, 173, 371–385.e18. [Google Scholar] [CrossRef] [Green Version]
- Kumar, S.; Warrell, J.; Li, S.; McGillivray, P.D.; Meyerson, W.; Salichos, L.; Harmanci, A.; Martinez-Fundichely, A.; Chan, C.W.Y.; Nielsen, M.M.; et al. Passenger Mutations in More Than 2500 Cancer Genomes: Overall Molecular Functional Impact and Consequences. Cell 2020, 180, 915–927.e16. [Google Scholar] [CrossRef]
- Cerami, E.; Gao, J.; Dogrusoz, U.; Gross, B.E.; Sumer, S.O.; Aksoy, B.A.; Jacobsen, A.; Byrne, C.J.; Heuer, M.L.; Larsson, E.; et al. The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012, 2, 401–404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Forbes, S.A.; Beare, D.; Boutselakis, H.; Bamford, S.; Bindal, N.; Tate, J.; Cole, C.G.; Ward, S.; Dawson, E.; Ponting, L.; et al. COSMIC: Somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017, 45, D777–D783. [Google Scholar] [CrossRef] [PubMed]
- Gao, J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 2013, 6, pl1. [Google Scholar] [CrossRef] [Green Version]
- Kusnadi, E.P.; Trigos, A.S.; Cullinane, C.; Goode, D.L.; Larsson, O.; Devlin, J.R.; Chan, K.T.; De Souza, D.P.; McConville, M.J.; McArthur, G.A.; et al. Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis. EMBO J. 2020, 39, e105111. [Google Scholar] [CrossRef] [PubMed]
- Hamilton, T.H. Isotopic studies on estrogen-induced accelerations of ribonucleic acid and protein synthesis. Proc. Natl. Acad. Sci. USA 1963, 49, 373–379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Noteboom, W.D.; Gorski, J. An Early Effect of Estrogen on Protein Synthesis. Proc. Natl. Acad. Sci. USA 1963, 50, 250–255. [Google Scholar] [CrossRef] [Green Version]
- Mueller, G.C.; Gorski, J.; Aizawa, Y. The role of protein synthesis in early estrogen action. Proc. Natl. Acad. Sci. USA 1961, 47, 164–169. [Google Scholar] [CrossRef] [Green Version]
- Schjeide, O.A.; Binz, S.; Ragan, N. Estrogen-Induced serum protein synthesis in the liver of the chicken embryo. Growth 1960, 24, 401–410. [Google Scholar]
- Schjeide, O.A.; Simons, S.; Ragan, N. Effect of x-irradiation on estrogen-induced protein synthesis in the chick. Growth 1959, 23, 273–290. [Google Scholar]
- Pennequin, P.; Robins, D.M.; Schimke, R.T. Regulation of translation of ovalbumin messenger RNA by estrogens and progesterone in oviduct of withdrawn chicks. Eur. J. Biochem. 1978, 90, 51–58. [Google Scholar] [CrossRef]
- Lu, Q.; Pallas, D.C.; Surks, H.K.; Baur, W.E.; Mendelsohn, M.E.; Karas, R.H. Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha. Proc. Natl. Acad. Sci. USA 2004, 101, 17126–17131. [Google Scholar] [CrossRef] [Green Version]
- Adlanmerini, M.; Solinhac, R.; Abot, A.; Fabre, A.; Raymond-Letron, I.; Guihot, A.L.; Boudou, F.; Sautier, L.; Vessieres, E.; Kim, S.H.; et al. Mutation of the palmitoylation site of estrogen receptor alpha in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc. Natl. Acad. Sci. USA 2014, 111, E283–E290. [Google Scholar] [CrossRef] [Green Version]
- Razandi, M.; Pedram, A.; Park, S.T.; Levin, E.R. Proximal events in signaling by plasma membrane estrogen receptors. J. Biol. Chem. 2003, 278, 2701–2712. [Google Scholar] [CrossRef] [Green Version]
- Song, R.X.; Zhang, Z.; Chen, Y.; Bao, Y.; Santen, R.J. Estrogen signaling via a linear pathway involving insulin-like growth factor I receptor, matrix metalloproteinases, and epidermal growth factor receptor to activate mitogen-activated protein kinase in MCF-7 breast cancer cells. Endocrinology 2007, 148, 4091–4101. [Google Scholar] [CrossRef] [Green Version]
- Bartucci, M.; Morelli, C.; Mauro, L.; Ando, S.; Surmacz, E. Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells. Cancer Res. 2001, 61, 6747–6754. [Google Scholar]
- Manavathi, B.; Acconcia, F.; Rayala, S.K.; Kumar, R. An inherent role of microtubule network in the action of nuclear receptor. Proc. Natl. Acad. Sci. USA 2006, 103, 15981–15986. [Google Scholar] [CrossRef] [Green Version]
- Hammes, S.R.; Levin, E.R. Extranuclear steroid receptors: Nature and actions. Endocr. Rev. 2007, 28, 726–741. [Google Scholar] [CrossRef]
- Chantalat, E.; Boudou, F.; Laurell, H.; Palierne, G.; Houtman, R.; Melchers, D.; Rochaix, P.; Filleron, T.; Stella, A.; Burlet-Schiltz, O.; et al. The AF-1-deficient estrogen receptor ERalpha46 isoform is frequently expressed in human breast tumors. Breast Cancer Res. 2016, 18, 123. [Google Scholar] [CrossRef] [Green Version]
- Silvera, D.; Formenti, S.C.; Schneider, R.J. Translational control in cancer. Nat. Rev. Cancer 2010, 10, 254–266. [Google Scholar] [CrossRef]
- Paul, M.R.; Pan, T.C.; Pant, D.K.; Shih, N.N.; Chen, Y.; Harvey, K.L.; Solomon, A.; Lieberman, D.; Morrissette, J.J.; Soucier-Ernst, D.; et al. Genomic landscape of metastatic breast cancer identifies preferentially dysregulated pathways and targets. J. Clin. Investig. 2020, 130, 4252–4265. [Google Scholar] [CrossRef] [PubMed]
- Adamo, B.; Deal, A.M.; Burrows, E.; Geradts, J.; Hamilton, E.; Blackwell, K.L.; Livasy, C.; Fritchie, K.; Prat, A.; Harrell, J.C.; et al. Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases. Breast Cancer Res. 2011, 13, R125. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brastianos, P.K.; Carter, S.L.; Santagata, S.; Cahill, D.P.; Taylor-Weiner, A.; Jones, R.T.; Van Allen, E.M.; Lawrence, M.S.; Horowitz, P.M.; Cibulskis, K.; et al. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov. 2015, 5, 1164–1177. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saunus, J.M.; Quinn, M.C.; Patch, A.M.; Pearson, J.V.; Bailey, P.J.; Nones, K.; McCart Reed, A.E.; Miller, D.; Wilson, P.J.; Al-Ejeh, F.; et al. Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance. J. Pathol. 2015, 237, 363–378. [Google Scholar] [CrossRef]
- Yu, J.; Henske, E.P. Estrogen-Induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Cancer Res. 2006, 66, 9461–9466. [Google Scholar] [CrossRef] [Green Version]
- Martin, E.C.; Rhodes, L.V.; Elliott, S.; Krebs, A.E.; Nephew, K.P.; Flemington, E.K.; Collins-Burow, B.M.; Burow, M.E. microRNA regulation of mammalian target of rapamycin expression and activity controls estrogen receptor function and RAD001 sensitivity. Mol. Cancer 2014, 13, 229. [Google Scholar] [CrossRef] [Green Version]
- Andruska, N.D.; Zheng, X.; Yang, X.; Mao, C.; Cherian, M.M.; Mahapatra, L.; Helferich, W.G.; Shapiro, D.J. Estrogen receptor alpha inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression. Proc. Natl. Acad. Sci. USA 2015, 112, 4737–4742. [Google Scholar] [CrossRef] [Green Version]
- Cuesta, R.; Gritsenko, M.A.; Petyuk, V.A.; Shukla, A.K.; Tsai, C.F.; Liu, T.; McDermott, J.E.; Holz, M.K. Phosphoproteome Analysis Reveals Estrogen-ER Pathway as a Modulator of mTOR Activity Via DEPTOR. Mol. Cell. Proteom. 2019, 18, 1607–1618. [Google Scholar] [CrossRef]
- Peterson, T.R.; Laplante, M.; Thoreen, C.C.; Sancak, Y.; Kang, S.A.; Kuehl, W.M.; Gray, N.S.; Sabatini, D.M. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009, 137, 873–886. [Google Scholar] [CrossRef] [Green Version]
- Chen, X.; Xiong, X.; Cui, D.; Yang, F.; Wei, D.; Li, H.; Shu, J.; Bi, Y.; Dai, X.; Gong, L.; et al. DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mTORC1/2 signals. Oncogene 2020, 39, 1557–1571. [Google Scholar] [CrossRef] [Green Version]
- Takizawa, I.; Lawrence, M.G.; Balanathan, P.; Rebello, R.; Pearson, H.B.; Garg, E.; Pedersen, J.; Pouliot, N.; Nadon, R.; Watt, M.J.; et al. Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity. Oncotarget 2015, 6, 604–616. [Google Scholar] [CrossRef] [Green Version]
- Xie, J.; Proud, C.G. Crosstalk between mTOR complexes. Nat. Cell Biol. 2013, 15, 1263–1265. [Google Scholar] [CrossRef]
- Xie, J.; Proud, C.G. Signaling crosstalk between the mTOR complexes. Translation 2014, 2, e28174. [Google Scholar] [CrossRef]
- Cuesta, R.; Berman, A.Y.; Alayev, A.; Holz, M.K. Estrogen receptor alpha promotes protein synthesis by fine-tuning the expression of the eukaryotic translation initiation factor 3 subunit f (eIF3f). J. Biol. Chem. 2019, 294, 2267–2278. [Google Scholar] [CrossRef] [Green Version]
- Zhang, L.; Pan, X.; Hershey, J.W. Individual overexpression of five subunits of human translation initiation factor eIF3 promotes malignant transformation of immortal fibroblast cells. J. Biol. Chem. 2007, 282, 5790–5800. [Google Scholar] [CrossRef] [Green Version]
- Martineau, Y.; Wang, X.; Alain, T.; Petroulakis, E.; Shahbazian, D.; Fabre, B.; Bousquet-Dubouch, M.P.; Monsarrat, B.; Pyronnet, S.; Sonenberg, N. Control of Paip1-eukayrotic translation initiation factor 3 interaction by amino acids through S6 kinase. Mol. Cell. Biol. 2014, 34, 1046–1053. [Google Scholar] [CrossRef] [Green Version]
- Holz, M.K.; Ballif, B.A.; Gygi, S.P.; Blenis, J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 2005, 123, 569–580. [Google Scholar] [CrossRef] [Green Version]
- Cenik, C.; Cenik, E.S.; Byeon, G.W.; Grubert, F.; Candille, S.I.; Spacek, D.; Alsallakh, B.; Tilgner, H.; Araya, C.L.; Tang, H.; et al. Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans. Genome Res. 2015, 25, 1610–1621. [Google Scholar] [CrossRef] [Green Version]
- Lorent, J.; Kusnadi, E.P.; van Hoef, V.; Rebello, R.J.; Leibovitch, M.; Ristau, J.; Chen, S.; Lawrence, M.G.; Szkop, K.J.; Samreen, B.; et al. Translational offsetting as a mode of estrogen receptor alpha-dependent regulation of gene expression. EMBO J. 2019, 38, e101323. [Google Scholar] [CrossRef] [PubMed]
- Castellano, L.; Giamas, G.; Jacob, J.; Coombes, R.C.; Lucchesi, W.; Thiruchelvam, P.; Barton, G.; Jiao, L.R.; Wait, R.; Waxman, J.; et al. The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response. Proc. Natl. Acad. Sci. USA 2009, 106, 15732–15737. [Google Scholar] [CrossRef] [Green Version]
- Maillot, G.; Lacroix-Triki, M.; Pierredon, S.; Gratadou, L.; Schmidt, S.; Benes, V.; Roche, H.; Dalenc, F.; Auboeuf, D.; Millevoi, S.; et al. Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. Cancer Res. 2009, 69, 8332–8340. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bailey, S.T.; Westerling, T.; Brown, M. Loss of estrogen-regulated microRNA expression increases HER2 signaling and is prognostic of poor outcome in luminal breast cancer. Cancer Res. 2015, 75, 436–445. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rapino, F.; Delaunay, S.; Rambow, F.; Zhou, Z.; Tharun, L.; De Tullio, P.; Sin, O.; Shostak, K.; Schmitz, S.; Piepers, J.; et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 2018, 558, 605–609. [Google Scholar] [CrossRef] [PubMed]
- Delaunay, S.; Rapino, F.; Tharun, L.; Zhou, Z.; Heukamp, L.; Termathe, M.; Shostak, K.; Klevernic, I.; Florin, A.; Desmecht, H.; et al. Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer. J. Exp. Med. 2016, 213, 2503–2523. [Google Scholar] [CrossRef] [Green Version]
- Ladang, A.; Rapino, F.; Heukamp, L.C.; Tharun, L.; Shostak, K.; Hermand, D.; Delaunay, S.; Klevernic, I.; Jiang, Z.; Jacques, N.; et al. Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine. J. Exp. Med. 2015, 212, 2057–2075. [Google Scholar] [CrossRef] [Green Version]
- Schalm, S.S.; Blenis, J. Identification of a conserved motif required for mTOR signaling. Curr. Biol. 2002, 12, 632–639. [Google Scholar] [CrossRef] [Green Version]
- Alayev, A.; Salamon, R.S.; Berger, S.M.; Schwartz, N.S.; Cuesta, R.; Snyder, R.B.; Holz, M.K. mTORC1 directly phosphorylates and activates ERalpha upon estrogen stimulation. Oncogene 2016, 35, 3535–3543. [Google Scholar] [CrossRef]
- Becker, M.A.; Ibrahim, Y.H.; Cui, X.; Lee, A.V.; Yee, D. The IGF pathway regulates ERalpha through a S6K1-dependent mechanism in breast cancer cells. Mol. Endocrinol. 2011, 25, 516–528. [Google Scholar] [CrossRef] [Green Version]
- Meric-Bernstam, F.; Chen, H.; Akcakanat, A.; Do, K.A.; Lluch, A.; Hennessy, B.T.; Hortobagyi, G.N.; Mills, G.B.; Gonzalez-Angulo, A. Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer. Breast Cancer Res. 2012, 14, R138. [Google Scholar] [CrossRef] [Green Version]
- Brunn, G.J.; Hudson, C.C.; Sekulic, A.; Williams, J.M.; Hosoi, H.; Houghton, P.J.; Lawrence, J.C., Jr.; Abraham, R.T. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997, 277, 99–101. [Google Scholar] [CrossRef]
- Rutkovsky, A.C.; Yeh, E.S.; Guest, S.T.; Findlay, V.J.; Muise-Helmericks, R.C.; Armeson, K.; Ethier, S.P. Eukaryotic initiation factor 4E-binding protein as an oncogene in breast cancer. BMC Cancer 2019, 19, 491. [Google Scholar] [CrossRef]
- Yanagiya, A.; Suyama, E.; Adachi, H.; Svitkin, Y.V.; Aza-Blanc, P.; Imataka, H.; Mikami, S.; Martineau, Y.; Ronai, Z.A.; Sonenberg, N. Translational homeostasis via the mRNA cap-binding protein, eIF4E. Mol. Cell 2012, 46, 847–858. [Google Scholar] [CrossRef] [Green Version]
- Parris, T.Z.; Ronnerman, E.W.; Engqvist, H.; Biermann, J.; Truve, K.; Nemes, S.; Forssell-Aronsson, E.; Solinas, G.; Kovacs, A.; Karlsson, P.; et al. Genome-Wide multi-omics profiling of the 8p11-p12 amplicon in breast carcinoma. Oncotarget 2018, 9, 24140–24154. [Google Scholar] [CrossRef] [Green Version]
- Lasorella, A.; Sanson, M.; Iavarone, A. FGFR-TACC gene fusions in human glioma. Neuro Oncol. 2017, 19, 475–483. [Google Scholar] [CrossRef] [Green Version]
- Brennan, C. FGFR-TACC approaches the first turn in the race for targetable GBM mutations. Neuro Oncol. 2017, 19, 461–462. [Google Scholar] [CrossRef] [Green Version]
- Williams-Ashman, H.G. Androgenic control of nucleic acid and protein synthesis in male accessory genital organs. J. Cell. Physiol. 1965, 66 (Suppl. 1), 111–124. [Google Scholar] [CrossRef]
- Liang, T.; Liao, S. A very rapid effect of androgen on initiation of protein synthesis in prostate. Proc. Natl. Acad. Sci. USA 1975, 72, 706–709. [Google Scholar] [CrossRef] [Green Version]
- Kochakian, C.D. Androgen Regulation of Nucleic Acid and Protein Biosynthesis in the Prostate. Natl. Cancer Inst. Monogr. 1963, 12, 263–274. [Google Scholar]
- Kochakian, C.D.; Hill, J.; Aonuma, S. Regulation of protein biosynthesis in mouse kidney by androgens. Endocrinology 1963, 72, 354–363. [Google Scholar] [CrossRef]
- Bernelli-Zazzera, A.; Bassi, M.; Comolli, R.; Lucchelli, P. Action of testosterone propionate and 4-chlorotestosterone acetate on protein synthesis in vitro. Nature 1958, 182, 663. [Google Scholar] [CrossRef]
- D’Abronzo, L.S.; Bose, S.; Crapuchettes, M.E.; Beggs, R.E.; Vinall, R.L.; Tepper, C.G.; Siddiqui, S.; Mudryj, M.; Melgoza, F.U.; Durbin-Johnson, B.P.; et al. The androgen receptor is a negative regulator of eIF4E phosphorylation at S209: Implications for the use of mTOR inhibitors in advanced prostate cancer. Oncogene 2017, 36, 6359–6373. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Q.; Bailey, C.G.; Ng, C.; Tiffen, J.; Thoeng, A.; Minhas, V.; Lehman, M.L.; Hendy, S.C.; Buchanan, G.; Nelson, C.C.; et al. Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res. 2011, 71, 7525–7536. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Holzbeierlein, J.; Lal, P.; LaTulippe, E.; Smith, A.; Satagopan, J.; Zhang, L.; Ryan, C.; Smith, S.; Scher, H.; Scardino, P.; et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am. J. Pathol. 2004, 164, 217–227. [Google Scholar] [CrossRef] [Green Version]
- Chandran, U.R.; Ma, C.; Dhir, R.; Bisceglia, M.; Lyons-Weiler, M.; Liang, W.; Michalopoulos, G.; Becich, M.; Monzon, F.A. Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process. BMC Cancer 2007, 7, 64. [Google Scholar] [CrossRef] [Green Version]
- Yu, Y.P.; Landsittel, D.; Jing, L.; Nelson, J.; Ren, B.; Liu, L.; McDonald, C.; Thomas, R.; Dhir, R.; Finkelstein, S.; et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J. Clin. Oncol. 2004, 22, 2790–2799. [Google Scholar] [CrossRef]
- Varambally, S.; Yu, J.; Laxman, B.; Rhodes, D.R.; Mehra, R.; Tomlins, S.A.; Shah, R.B.; Chandran, U.; Monzon, F.A.; Becich, M.J.; et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 2005, 8, 393–406. [Google Scholar] [CrossRef] [Green Version]
- Jin, Y.; Qu, S.; Tesikova, M.; Wang, L.; Kristian, A.; Maelandsmo, G.M.; Kong, H.; Zhang, T.; Jeronimo, C.; Teixeira, M.R.; et al. Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer. Proc. Natl. Acad. Sci. USA 2013, 110, E2572–E2581. [Google Scholar] [CrossRef] [Green Version]
- Velasco, A.M.; Gillis, K.A.; Li, Y.; Brown, E.L.; Sadler, T.M.; Achilleos, M.; Greenberger, L.M.; Frost, P.; Bai, W.; Zhang, Y. Identification and validation of novel androgen-regulated genes in prostate cancer. Endocrinology 2004, 145, 3913–3924. [Google Scholar] [CrossRef] [Green Version]
- Wang, L. FKBP51 regulation of AKT/protein kinase B phosphorylation. Curr. Opin. Pharmacol. 2011, 11, 360–364. [Google Scholar] [CrossRef] [Green Version]
- Wang, Y.; Mikhailova, M.; Bose, S.; Pan, C.X.; deVere White, R.W.; Ghosh, P.M. Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene 2008, 27, 7106–7117. [Google Scholar] [CrossRef] [Green Version]
- Sarbassov, D.D.; Ali, S.M.; Sengupta, S.; Sheen, J.H.; Hsu, P.P.; Bagley, A.F.; Markhard, A.L.; Sabatini, D.M. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 2006, 22, 159–168. [Google Scholar] [CrossRef]
- Xie, J.; Wang, X.; Proud, C.G. mTOR inhibitors in cancer therapy. F1000Research 2016, 5. [Google Scholar] [CrossRef] [Green Version]
- Audet-Walsh, E.; Dufour, C.R.; Yee, T.; Zouanat, F.Z.; Yan, M.; Kalloghlian, G.; Vernier, M.; Caron, M.; Bourque, G.; Scarlata, E.; et al. Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer. Genes Dev. 2017, 31, 1228–1242. [Google Scholar] [CrossRef] [Green Version]
- Giguere, V. DNA-PK, Nuclear mTOR, and the Androgen Pathway in Prostate Cancer. Trends Cancer 2020, 6, 337–347. [Google Scholar] [CrossRef]
- Audet-Walsh, E.; Vernier, M.; Yee, T.; Laflamme, C.; Li, S.; Chen, Y.; Giguere, V. SREBF1 Activity Is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer. Mol. Cancer Res. 2018, 16, 1396–1405. [Google Scholar] [CrossRef] [Green Version]
- Gonzalez-Herrera, I.G.; Prado-Lourenco, L.; Pileur, F.; Conte, C.; Morin, A.; Cabon, F.; Prats, H.; Vagner, S.; Bayard, F.; Audigier, S.; et al. Testosterone regulates FGF-2 expression during testis maturation by an IRES-dependent translational mechanism. FASEB J. 2006, 20, 476–478. [Google Scholar] [CrossRef] [Green Version]
- Sheng, X.; Arnoldussen, Y.J.; Storm, M.; Tesikova, M.; Nenseth, H.Z.; Zhao, S.; Fazli, L.; Rennie, P.; Risberg, B.; Waehre, H.; et al. Divergent androgen regulation of unfolded protein response pathways drives prostate cancer. EMBO Mol. Med. 2015, 7, 788–801. [Google Scholar] [CrossRef]
- Segawa, T.; Nau, M.E.; Xu, L.L.; Chilukuri, R.N.; Makarem, M.; Zhang, W.; Petrovics, G.; Sesterhenn, I.A.; McLeod, D.G.; Moul, J.W.; et al. Androgen-Induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells. Oncogene 2002, 21, 8749–8758. [Google Scholar] [CrossRef] [Green Version]
- Sheng, X.; Nenseth, H.Z.; Qu, S.; Kuzu, O.F.; Frahnow, T.; Simon, L.; Greene, S.; Zeng, Q.; Fazli, L.; Rennie, P.S.; et al. IRE1alpha-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat. Commun. 2019, 10, 323. [Google Scholar] [CrossRef] [Green Version]
- Stelloo, S.; Linder, S.; Nevedomskaya, E.; Valle-Encinas, E.; de Rink, I.; Wessels, L.F.A.; van der Poel, H.; Bergman, A.M.; Zwart, W. Androgen modulation of XBP1 is functionally driving part of the AR transcriptional program. Endocr. Relat. Cancer 2020, 27, 67–79. [Google Scholar] [CrossRef]
- Erzurumlu, Y.; Ballar, P. Androgen Mediated Regulation of Endoplasmic Reticulum-Associated Degradation and its Effects on Prostate Cancer. Sci. Rep. 2017, 7, 40719. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, Y.C.; Fu, H.C.; Hsiao, B.L.; Sobue, G.; Adachi, H.; Huang, F.J.; Hsuuw, Y.D.; Wei, K.T.; Chang, C.; Huang, K.E.; et al. Androgen receptor inclusions acquire GRP78/BiP to ameliorate androgen-induced protein misfolding stress in embryonic stem cells. Cell Death Dis. 2013, 4, e607. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Azhary, J.M.K.; Harada, M.; Takahashi, N.; Nose, E.; Kunitomi, C.; Koike, H.; Hirata, T.; Hirota, Y.; Koga, K.; Wada-Hiraike, O.; et al. Endoplasmic Reticulum Stress Activated by Androgen Enhances Apoptosis of Granulosa Cells via Induction of Death Receptor 5 in PCOS. Endocrinology 2019, 160, 119–132. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Doultsinos, D.; Mills, I. The role of the androgen receptor as a driver and mitigator of cellular stress. J. Mol. Endocrinol. 2020, 65, R19–R33. [Google Scholar] [CrossRef] [PubMed]
- Isakoff, S.J.; Engelman, J.A.; Irie, H.Y.; Luo, J.; Brachmann, S.M.; Pearline, R.V.; Cantley, L.C.; Brugge, J.S. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005, 65, 10992–11000. [Google Scholar] [CrossRef] [Green Version]
- Zhang, H.; Liu, G.; Dziubinski, M.; Yang, Z.; Ethier, S.P.; Wu, G. Comprehensive analysis of oncogenic effects of PIK3CA mutations in human mammary epithelial cells. Breast Cancer Res. Treat. 2008, 112, 217–227. [Google Scholar] [CrossRef]
- Crowder, R.J.; Phommaly, C.; Tao, Y.; Hoog, J.; Luo, J.; Perou, C.M.; Parker, J.S.; Miller, M.A.; Huntsman, D.G.; Lin, L.; et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009, 69, 3955–3962. [Google Scholar] [CrossRef] [Green Version]
- O’Brien, N.A.; McDonald, K.; Tong, L.; von Euw, E.; Kalous, O.; Conklin, D.; Hurvitz, S.A.; di Tomaso, E.; Schnell, C.; Linnartz, R.; et al. Targeting PI3K/mTOR overcomes resistance to HER2-targeted therapy independent of feedback activation of AKT. Clin. Cancer Res. 2014, 20, 3507–3520. [Google Scholar] [CrossRef] [Green Version]
- Kalinsky, K.; Jacks, L.M.; Heguy, A.; Patil, S.; Drobnjak, M.; Bhanot, U.K.; Hedvat, C.V.; Traina, T.A.; Solit, D.; Gerald, W.; et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin. Cancer Res. 2009, 15, 5049–5059. [Google Scholar] [CrossRef] [Green Version]
- Loi, S.; Haibe-Kains, B.; Majjaj, S.; Lallemand, F.; Durbecq, V.; Larsimont, D.; Gonzalez-Angulo, A.M.; Pusztai, L.; Symmans, W.F.; Bardelli, A.; et al. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc. Natl. Acad. Sci. USA 2010, 107, 10208–10213. [Google Scholar] [CrossRef] [Green Version]
- The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012, 490, 61–70. [Google Scholar] [CrossRef] [Green Version]
- Coussy, F.; Lavigne, M.; de Koning, L.; Botty, R.E.; Nemati, F.; Naguez, A.; Bataillon, G.; Ouine, B.; Dahmani, A.; Montaudon, E.; et al. Response to mTOR and PI3K inhibitors in enzalutamide-resistant luminal androgen receptor triple-negative breast cancer patient-derived xenografts. Theranostics 2020, 10, 1531–1543. [Google Scholar] [CrossRef]
- Verret, B.; Cortes, J.; Bachelot, T.; Andre, F.; Arnedos, M. Efficacy of PI3K inhibitors in advanced breast cancer. Ann. Oncol. 2019, 30 (Suppl. 10), x12–x20. [Google Scholar] [CrossRef]
- Shorning, B.Y.; Dass, M.S.; Smalley, M.J.; Pearson, H.B. The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. Int. J. Mol. Sci. 2020, 21, 4507. [Google Scholar] [CrossRef]
- Braglia, L.; Zavatti, M.; Vinceti, M.; Martelli, A.M.; Marmiroli, S. Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target? Biochim. Biophys. Acta Mol. Cell Res. 2020, 1867, 118731. [Google Scholar] [CrossRef]
- Park, S.; Kim, Y.S.; Kim, D.Y.; So, I.; Jeon, J.H. PI3K pathway in prostate cancer: All resistant roads lead to PI3K. Biochim. Biophys. Acta Rev. Cancer 2018, 1870, 198–206. [Google Scholar] [CrossRef]
- Mbatia, H.W.; Ramalingam, S.; Ramamurthy, V.P.; Martin, M.S.; Kwegyir-Afful, A.K.; Njar, V.C. Novel C-4 heteroaryl 13-cis-retinamide Mnk/AR degrading agents inhibit cell proliferation and migration and induce apoptosis in human breast and prostate cancer cells and suppress growth of MDA-MB-231 human breast and CWR22Rv1 human prostate tumor xenografts in mice. J. Med. Chem. 2015, 58, 1900–1914. [Google Scholar] [CrossRef]
- Ramamurthy, V.P.; Ramalingam, S.; Gediya, L.; Kwegyir-Afful, A.K.; Njar, V.C. Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines. Oncotarget 2015, 6, 3195–3210. [Google Scholar] [CrossRef] [Green Version]
- Xie, J.; Shen, K.; Jones, A.T.; Yang, J.; Tee, A.R.; Shen, M.H.; Yu, M.; Irani, S.; Wong, D.; Merrett, J.E.; et al. Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis. Cell. Mol. Life Sci. 2020, 249–270. [Google Scholar] [CrossRef]
- Stead, R.L.; Proud, C.G. Rapamycin enhances eIF4E phosphorylation by activating MAP kinase-interacting kinase 2a (Mnk2a). FEBS Lett. 2013, 587, 2623–2628. [Google Scholar] [CrossRef] [Green Version]
- Reich, S.H.; Sprengeler, P.A.; Chiang, G.G.; Appleman, J.R.; Chen, J.; Clarine, J.; Eam, B.; Ernst, J.T.; Han, Q.; Goel, V.K.; et al. Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition. J. Med. Chem. 2018, 61, 3516–3540. [Google Scholar] [CrossRef] [PubMed]
- Geter, P.A.; Ernlund, A.W.; Bakogianni, S.; Alard, A.; Arju, R.; Giashuddin, S.; Gadi, A.; Bromberg, J.; Schneider, R.J. Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming. Genes Dev. 2017, 31, 2235–2249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bain, J.; Plater, L.; Elliott, M.; Shpiro, N.; Hastie, C.J.; McLauchlan, H.; Klevernic, I.; Arthur, J.S.; Alessi, D.R.; Cohen, P. The selectivity of protein kinase inhibitors: A further update. Biochem. J. 2007, 408, 297–315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Truitt, M.L.; Conn, C.S.; Shi, Z.; Pang, X.; Tokuyasu, T.; Coady, A.M.; Seo, Y.; Barna, M.; Ruggero, D. Differential Requirements for eIF4E Dose in Normal Development and Cancer. Cell 2015, 162, 59–71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Furic, L.; Rong, L.; Larsson, O.; Koumakpayi, I.H.; Yoshida, K.; Brueschke, A.; Petroulakis, E.; Robichaud, N.; Pollak, M.; Gaboury, L.A.; et al. eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc. Natl. Acad. Sci. USA 2010, 107, 14134–14139. [Google Scholar] [CrossRef] [Green Version]
- Hsieh, A.C.; Liu, Y.; Edlind, M.P.; Ingolia, N.T.; Janes, M.R.; Sher, A.; Shi, E.Y.; Stumpf, C.R.; Christensen, C.; Bonham, M.J.; et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012, 485, 55–61. [Google Scholar] [CrossRef] [Green Version]
- Yang, H.S.; Jansen, A.P.; Komar, A.A.; Zheng, X.; Merrick, W.C.; Costes, S.; Lockett, S.J.; Sonenberg, N.; Colburn, N.H. The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. Mol. Cell. Biol. 2003, 23, 26–37. [Google Scholar] [CrossRef] [Green Version]
- Howard, C.M.; Estrada, M.; Terrero, D.; Tiwari, A.K.; Raman, D. Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells. Cancers 2020, 12, 2169. [Google Scholar] [CrossRef]
- Sridharan, S.; Robeson, M.; Bastihalli-Tukaramrao, D.; Howard, C.M.; Subramaniyan, B.; Tilley, A.M.C.; Tiwari, A.K.; Raman, D. Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness. Front. Oncol. 2019, 9, 1311. [Google Scholar] [CrossRef] [Green Version]
- Cencic, R.; Carrier, M.; Galicia-Vazquez, G.; Bordeleau, M.E.; Sukarieh, R.; Bourdeau, A.; Brem, B.; Teodoro, J.G.; Greger, H.; Tremblay, M.L.; et al. Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLoS ONE 2009, 4, e5223. [Google Scholar] [CrossRef] [Green Version]
- Garrido, M.F.; Martin, N.J.; Bertrand, M.; Gaudin, C.; Commo, F.; El Kalaany, N.; Al Nakouzi, N.; Fazli, L.; Del Nery, E.; Camonis, J.; et al. Regulation of eIF4F Translation Initiation Complex by the Peptidyl Prolyl Isomerase FKBP7 in Taxane-resistant Prostate Cancer. Clin. Cancer Res. 2019, 25, 710–723. [Google Scholar] [CrossRef] [Green Version]
- Modelska, A.; Turro, E.; Russell, R.; Beaton, J.; Sbarrato, T.; Spriggs, K.; Miller, J.; Graf, S.; Provenzano, E.; Blows, F.; et al. The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape. Cell Death Dis. 2015, 6, e1603. [Google Scholar] [CrossRef] [Green Version]
- Nasr, Z.; Robert, F.; Porco, J.A., Jr.; Muller, W.J.; Pelletier, J. eIF4F suppression in breast cancer affects maintenance and progression. Oncogene 2013, 32, 861–871. [Google Scholar] [CrossRef] [Green Version]
- Jin, C.; Rajabi, H.; Rodrigo, C.M.; Porco, J.A., Jr.; Kufe, D. Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein. Oncogene 2013, 32, 2179–2188. [Google Scholar] [CrossRef] [Green Version]
- Nguyen, T.M.; Kabotyanski, E.B.; Dou, Y.; Reineke, L.C.; Zhang, P.; Zhang, X.H.; Malovannaya, A.; Jung, S.Y.; Mo, Q.; Roarty, K.P.; et al. FGFR1-Activated Translation of WNT Pathway Components with Structured 5′ UTRs Is Vulnerable to Inhibition of EIF4A-Dependent Translation Initiation. Cancer Res. 2018, 78, 4229–4240. [Google Scholar] [CrossRef] [Green Version]
- Ernst, J.T.; Thompson, P.A.; Nilewski, C.; Sprengeler, P.A.; Sperry, S.; Packard, G.; Michels, T.; Xiang, A.; Tran, C.; Wegerski, C.J.; et al. Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase. J. Med. Chem. 2020, 63, 5879–5955. [Google Scholar] [CrossRef]
- Rubio, C.A.; Weisburd, B.; Holderfield, M.; Arias, C.; Fang, E.; DeRisi, J.L.; Fanidi, A. Transcriptome-Wide characterization of the eIF4A signature highlights plasticity in translation regulation. Genome Biol. 2014, 15, 476. [Google Scholar] [CrossRef]
- Ebright, R.Y.; Lee, S.; Wittner, B.S.; Niederhoffer, K.L.; Nicholson, B.T.; Bardia, A.; Truesdell, S.; Wiley, D.F.; Wesley, B.; Li, S.; et al. Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis. Science 2020, 367, 1468–1473. [Google Scholar] [CrossRef]
- Rebello, R.J.; Kusnadi, E.; Cameron, D.P.; Pearson, H.B.; Lesmana, A.; Devlin, J.R.; Drygin, D.; Clark, A.K.; Porter, L.; Pedersen, J.; et al. The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer. Clin. Cancer Res. 2016, 22, 5539–5552. [Google Scholar] [CrossRef] [Green Version]
- Lawrence, M.G.; Obinata, D.; Sandhu, S.; Selth, L.A.; Wong, S.Q.; Porter, L.H.; Lister, N.; Pook, D.; Pezaro, C.J.; Goode, D.L.; et al. Patient-Derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy. Eur. Urol. 2018, 74, 562–572. [Google Scholar] [CrossRef]
- Nguyen, H.G.; Conn, C.S.; Kye, Y.; Xue, L.; Forester, C.M.; Cowan, J.E.; Hsieh, A.C.; Cunningham, J.T.; Truillet, C.; Tameire, F.; et al. Development of a stress response therapy targeting aggressive prostate cancer. Sci. Transl. Med. 2018, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sidrauski, C.; Acosta-Alvear, D.; Khoutorsky, A.; Vedantham, P.; Hearn, B.R.; Li, H.; Gamache, K.; Gallagher, C.M.; Ang, K.K.; Wilson, C.; et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2013, 2, e00498. [Google Scholar] [CrossRef] [PubMed]
- Bain, J.; McLauchlan, H.; Elliott, M.; Cohen, P. The specificities of protein kinase inhibitors: An update. Biochem. J. 2003, 371, 199–204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Davies, S.P.; Reddy, H.; Caivano, M.; Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 2000, 351, 95–105. [Google Scholar] [CrossRef] [PubMed]
- Alain, T.; Morita, M.; Fonseca, B.D.; Yanagiya, A.; Siddiqui, N.; Bhat, M.; Zammit, D.; Marcus, V.; Metrakos, P.; Voyer, L.A.; et al. eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Res. 2012, 72, 6468–6476. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chan, S.; Scheulen, M.E.; Johnston, S.; Mross, K.; Cardoso, F.; Dittrich, C.; Eiermann, W.; Hess, D.; Morant, R.; Semiglazov, V.; et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J. Clin. Oncol. 2005, 23, 5314–5322. [Google Scholar] [CrossRef]
- Awada, A.; Cardoso, F.; Fontaine, C.; Dirix, L.; De Greve, J.; Sotiriou, C.; Steinseifer, J.; Wouters, C.; Tanaka, C.; Zoellner, U.; et al. The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: Results of a phase I study with pharmacokinetics. Eur. J. Cancer 2008, 44, 84–91. [Google Scholar] [CrossRef]
- Ellard, S.L.; Clemons, M.; Gelmon, K.A.; Norris, B.; Kennecke, H.; Chia, S.; Pritchard, K.; Eisen, A.; Vandenberg, T.; Taylor, M.; et al. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J. Clin. Oncol. 2009, 27, 4536–4541. [Google Scholar] [CrossRef]
- Zagouri, F.; Sergentanis, T.N.; Chrysikos, D.; Filipits, M.; Bartsch, R. mTOR inhibitors in breast cancer: A systematic review. Gynecol. Oncol. 2012, 127, 662–672. [Google Scholar] [CrossRef]
- Baselga, J.; Campone, M.; Piccart, M.; Burris, H.A., 3rd; Rugo, H.S.; Sahmoud, T.; Noguchi, S.; Gnant, M.; Pritchard, K.I.; Lebrun, F.; et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 2012, 366, 520–529. [Google Scholar] [CrossRef] [Green Version]
- Piccart, M.; Hortobagyi, G.N.; Campone, M.; Pritchard, K.I.; Lebrun, F.; Ito, Y.; Noguchi, S.; Perez, A.; Rugo, H.S.; Deleu, I.; et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Overall survival results from BOLERO-2dagger. Ann. Oncol. 2014, 25, 2357–2362. [Google Scholar] [CrossRef]
- Wolff, A.C.; Lazar, A.A.; Bondarenko, I.; Garin, A.M.; Brincat, S.; Chow, L.; Sun, Y.; Neskovic-Konstantinovic, Z.; Guimaraes, R.C.; Fumoleau, P.; et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J. Clin. Oncol. 2013, 31, 195–202. [Google Scholar] [CrossRef] [Green Version]
- Kornblum, N.; Zhao, F.; Manola, J.; Klein, P.; Ramaswamy, B.; Brufsky, A.; Stella, P.J.; Burnette, B.; Telli, M.; Makower, D.F.; et al. Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102. J. Clin. Oncol. 2018, 36, 1556–1563. [Google Scholar] [CrossRef]
- Armstrong, A.J.; Netto, G.J.; Rudek, M.A.; Halabi, S.; Wood, D.P.; Creel, P.A.; Mundy, K.; Davis, S.L.; Wang, T.; Albadine, R.; et al. A pharmacodynamic study of rapamycin in men with intermediate-to high-risk localized prostate cancer. Clin. Cancer Res. 2010, 16, 3057–3066. [Google Scholar] [CrossRef] [Green Version]
- Nakabayashi, M.; Werner, L.; Courtney, K.D.; Buckle, G.; Oh, W.K.; Bubley, G.J.; Hayes, J.H.; Weckstein, D.; Elfiky, A.; Sims, D.M.; et al. Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer. BJU Int. 2012, 110, 1729–1735. [Google Scholar] [CrossRef]
- Kruczek, K.; Ratterman, M.; Tolzien, K.; Sulo, S.; Lestingi, T.M.; Nabhan, C. A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naive castration-resistant prostate cancer. Br. J. Cancer 2013, 109, 1711–1716. [Google Scholar] [CrossRef] [Green Version]
- Templeton, A.J.; Dutoit, V.; Cathomas, R.; Rothermundt, C.; Bartschi, D.; Droge, C.; Gautschi, O.; Borner, M.; Fechter, E.; Stenner, F.; et al. Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08). Eur. Urol. 2013, 64, 150–158. [Google Scholar] [CrossRef]
- Wei, X.X.; Hsieh, A.C.; Kim, W.; Friedlander, T.; Lin, A.M.; Louttit, M.; Ryan, C.J. A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer. Oncologist 2017, 22, e503–e543. [Google Scholar] [CrossRef] [Green Version]
- Massard, C.; Chi, K.N.; Castellano, D.; de Bono, J.; Gravis, G.; Dirix, L.; Machiels, J.P.; Mita, A.; Mellado, B.; Turri, S.; et al. Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer. Eur. J. Cancer 2017, 76, 36–44. [Google Scholar] [CrossRef]
- Graham, L.; Banda, K.; Torres, A.; Carver, B.S.; Chen, Y.; Pisano, K.; Shelkey, G.; Curley, T.; Scher, H.I.; Lotan, T.L.; et al. A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer. Investig. New Drugs 2018, 36, 458–467. [Google Scholar] [CrossRef]
- Koshkin, V.S.; Mir, M.C.; Barata, P.; Gul, A.; Gupta, R.; Stephenson, A.J.; Kaouk, J.; Berglund, R.; Magi-Galluzzi, C.; Klein, E.A.; et al. Randomized phase II trial of neoadjuvant everolimus in patients with high-risk localized prostate cancer. Investig. New Drugs 2019, 37, 559–566. [Google Scholar] [CrossRef]
- Barata, P.C.; Cooney, M.; Mendiratta, P.; Gupta, R.; Dreicer, R.; Garcia, J.A. Phase I/II study evaluating the safety and clinical efficacy of temsirolimus and bevacizumab in patients with chemotherapy refractory metastatic castration-resistant prostate cancer. Investig. New Drugs 2019, 37, 331–337. [Google Scholar] [CrossRef]
- Thoreen, C.C.; Sabatini, D.M. Rapamycin inhibits mTORC1, but not completely. Autophagy 2009, 5, 725–726. [Google Scholar] [CrossRef] [Green Version]
- Thoreen, C.C.; Kang, S.A.; Chang, J.W.; Liu, Q.; Zhang, J.; Gao, Y.; Reichling, L.J.; Sim, T.; Sabatini, D.M.; Gray, N.S. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 2009, 284, 8023–8032. [Google Scholar] [CrossRef] [Green Version]
- Yang, W.; Schwartz, G.N.; Marotti, J.D.; Chen, V.; Traphagen, N.A.; Gui, J.; Miller, T.W. Estrogen receptor alpha drives mTORC1 inhibitor-induced feedback activation of PI3K/AKT in ER+ breast cancer. Oncotarget 2018, 9, 8810–8822. [Google Scholar] [CrossRef] [Green Version]
- Shee, K.; Yang, W.; Hinds, J.W.; Hampsch, R.A.; Varn, F.S.; Traphagen, N.A.; Patel, K.; Cheng, C.; Jenkins, N.P.; Kettenbach, A.N.; et al. Therapeutically targeting tumor microenvironment-mediated drug resistance in estrogen receptor-positive breast cancer. J. Exp. Med. 2018, 215, 895–910. [Google Scholar] [CrossRef] [Green Version]
- Barlow, A.D.; Xie, J.; Moore, C.E.; Campbell, S.C.; Shaw, J.A.; Nicholson, M.L.; Herbert, T.P. Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2). Diabetologia 2012, 55, 1355–1365. [Google Scholar] [CrossRef] [Green Version]
- Croessmann, S.; Formisano, L.; Kinch, L.N.; Gonzalez-Ericsson, P.I.; Sudhan, D.R.; Nagy, R.J.; Mathew, A.; Bernicker, E.H.; Cristofanilli, M.; He, J.; et al. Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer. Clin. Cancer Res. 2019, 25, 277–289. [Google Scholar] [CrossRef] [Green Version]
- Heffron, T.P.; Ndubaku, C.O.; Salphati, L.; Alicke, B.; Cheong, J.; Drobnick, J.; Edgar, K.; Gould, S.E.; Lee, L.B.; Lesnick, J.D.; et al. Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR. ACS Med. Chem. Lett. 2016, 7, 351–356. [Google Scholar] [CrossRef] [Green Version]
- Ippen, F.M.; Alvarez-Breckenridge, C.A.; Kuter, B.M.; Fink, A.L.; Bihun, I.V.; Lastrapes, M.; Penson, T.; Schmidt, S.P.; Wojtkiewicz, G.R.; Ning, J.; et al. The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in PIK3CA-Mutant Breast Cancer Brain Metastases. Clin. Cancer Res. 2019, 25, 3374–3383. [Google Scholar] [CrossRef] [Green Version]
- La Manna, F.; De Menna, M.; Patel, N.; Karkampouna, S.; De Filippo, M.; Klima, I.; Kloen, P.; Beimers, L.; Thalmann, G.N.; Pelger, R.C.M.; et al. Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity. Front. Oncol. 2020, 10, 1012. [Google Scholar] [CrossRef] [PubMed]
Gene | BC (Invasive Carcinoma, 1084 Samples) | PC (494 Samples) | ||
---|---|---|---|---|
No. of Mutated Samples | % of Mutated Samples | No. of Mutated Samples | % of Mutated Samples | |
AKT1 | 27 | 2.49% | 2 | 0.40% |
AKT2 | 4 | 0.37% | 0 | 0.00% |
AKT3 | 8 | 0.74% | 1 | 0.20% |
BRAF | 7 | 0.65% | 7 | 1.42% |
CRAF | 7 | 0.65% | 0 | 0.00% |
HRAS | 5 | 0.46% | 4 | 0.81% |
KRAS | 6 | 0.55% | 2 | 0.40% |
MAP2K4 | 7 | 0.65% | 1 | 0.20% |
MAP3K1 | 7 | 0.65% | 1 | 0.20% |
MTOR | 20 | 1.85% | 2 | 0.40% |
PIK3CA | 333 | 30.72% | 10 | 2.02% |
PIK3CB | 10 | 0.92% | 3 | 0.61% |
PIK3CD | 11 | 1.01% | 2 | 0.40% |
PTEN | 56 | 5.17% | 13 | 2.63% |
Year | Cancer Type | Drug(s) | Gen. | Phase | Outcome Summary | Ref. |
---|---|---|---|---|---|---|
2005 | Localized or metastatic BC | Temsirolimus (CCI-779) only | 1st | II | Patients treated with temsirolimus showed anti-tumour activity and well tolerated toxicity. | [176] |
2008 | Advanced BC | Everolimus (RAD001) and letrozole | 1st | I | The combinational therapy showed anti-tumour activity, toxicity also well tolerated. | [177] |
2009 | Recurrent or metastatic BC | Everolimus only | 1st | II | Continuous daily dosing but not weekly dosing had anti-tumour activity. The drug was well tolerated but some patients developed pneumonitis. | [178] |
2010 | Localized PC | Sirolimus (rapamycin) only | 1st | I | Daily dosing had no effect on tumour proliferation/apoptosis despite suppresion of RP S6 phsophorylation. | [184] |
2012 | CRPC | Everolimus and bicalutamide | 1st | II | Combinational therapy was well tolerated despite 56% cases of grade 1/2 mucositis, but it had low activity and did not achieve the primary endpoint. | [185] |
2012 | HR+ BC | Everolimus and exemestane | 1st | III, FA | Combinational therapy improved PFS of patients previously treated with non-steroidal AIs. | [180] |
2013 | Locally advanced or metastatic BC | Temsirolimus and letrozole | 1st | III | In comparison to lotrozole monotherapy, daily and orally administrated temsirolimus failed to confer added PFS benefit to aromatase inhibitor-resistant ER+ patients. | [182] |
2013 | CRPC | Temsirolimus only | 1st | II | Weekly dosing of the drug had minimal therapeutic activity, and the study was put on halt at an early stage. | [186] |
2013 | CRPC | Everolimus only | 1st | II | The monotherapy regime modestly improved PFS, especially in PTEN−/− patients. Toxicity was also manageable. | [187] |
2014 | Advanced BC | Everolimus and exemestane | 1st | III | Addition of everolimus to exemestane treatment did not provide further improvement to HR+ BC patients at the secondary endpoint. | [181] |
2017 | CRPC | BEZ235 with abiraterone/prednisone | DI | I | The combinational therapy was poorly tolerated; adverse effects included mucositis, hypotension, dyspnea and pneumonitis. | [188] |
2017 | CRPC | BEZ235/BKM120 with abiraterone | DI | Ib | The trial was discontinued due to high levels of toxicity and poor pharmacokinetics among the participants. | [189] |
2018 | CRPC | MLN0128 (INK128) | 2nd | II | MLN0128 exhibited high levels of toxicity in patients; dyspnea and maculopapular rash were the main grade 3 adverse events. | [190] |
2018 | ER+/EGFR2−BC | Everolimus and fulvestrant | 1st | II | Despite increased cases of adverse events, improved PFS was observed with combinational therapy-treated patients. | [183] |
2019 | High-risk localized PC | Everolimus | 1st | II | Everolimus showed limited clinical activity. | [191] |
2019 | CRPC | Temsirolimus and bevacizumab | 1st | I/II | The combinational therapy did not improve the clinical outcome of the participants, and also induced severe adverse events. | [192] |
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Xie, J.; Kusnadi, E.P.; Furic, L.; Selth, L.A. Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer. Cancers 2021, 13, 3254. https://doi.org/10.3390/cancers13133254
Xie J, Kusnadi EP, Furic L, Selth LA. Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer. Cancers. 2021; 13(13):3254. https://doi.org/10.3390/cancers13133254
Chicago/Turabian StyleXie, Jianling, Eric P. Kusnadi, Luc Furic, and Luke A. Selth. 2021. "Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer" Cancers 13, no. 13: 3254. https://doi.org/10.3390/cancers13133254