Reactivation of the PI3K/mTOR Signaling Pathway Confers Resistance to the FGFR4 Inhibitor FGF401
Abstract
1. Introduction
2. Results
2.1. Prolonged Treatment with FGF401 Resulted in the Emergence of FGF401 Resistance
2.2. Dose-Dependent Inhibition of FGF401/Everolimus Growth
2.3. FGF401/Everolimus Combination Reverses Resistance to FGF401
2.4. FGF401/Everolimus Exerts Long-Lasting Tumor Growth Inhibition in PDX Models Expressing FGF19/FGFR4 or Both FGF19/FGFR4 and Activated mTOR
2.5. Effects of FGF401, Everolimus, and FGF401/Everolimus on Liver and Kidney Injury-Related Parameters
2.6. Everolimus Synergizes with FGF401 to Normalize Blood Vessels, Inhibit Cell Proliferation, and Promote Tumor Cell Apoptosis in HCC Models
2.7. Everolimus Abrogated FGF401-Induced Activation of mTOR but Not MEK/ERK Pathways
2.8. FGF401/Everolimus Prolongs the Survival of Mice Bearing HCC Orthotopic Tumors
3. Discussion
4. Materials and Methods
4.1. Reagents
4.2. HCC Patient-Derived Xenograft (PDX) Models
4.3. Development of the FGF401-Resistant HCC25–0705A–FGF401–R3 Model
4.4. Efficacy of FGF401/Everolimus in Ectopic HCC Models
4.5. Efficacy of FGF401, Everolimus, and FGF401/Everolimus in Orthotopic HCC Models
4.6. Western Blot Analysis and Quantification Analysis
4.7. Serum Analysis
4.8. Immunohistochemistry (IHC)
4.9. Vessel Perfusion and Hypoxia Studies
4.10. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Rumgay, H.; Arnold, M.; Ferlay, J.; Lesi, O.; Cabasag, C.J.; Vignat, J.; Laversanne, M.; McGlynn, K.A.; Soerjomataram, I. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022, 77, 1598–1606. [Google Scholar] [CrossRef]
- Désert, R.; Nieto, N.; Musso, O. Dimensions of hepatocellular carcinoma phenotypic diversity. World J. Gastroenterol. 2018, 24, 4536–4547. [Google Scholar] [CrossRef] [PubMed]
- Okuda, K.; Ohtsuki, T.; Obata, H.; Tomimatsu, M.; Okazaki, N.; Hasegawa, H.; Nakajima, Y.; Ohnishi, K. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985, 56, 918–928. [Google Scholar] [CrossRef] [PubMed]
- Llovet, J.M.; Burroughs, A.; Bruix, J. Hepatocellular carcinoma. Lancet 2003, 362, 1907–1917. [Google Scholar] [CrossRef]
- Bruix, J.; Sherman, M.; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: An update. Hepatology 2011, 53, 1020–1022. [Google Scholar] [CrossRef]
- Cheng, A.-L.; Kang, Y.-K.; Chen, Z.; Tsao, C.-J.; Qin, S.; Kim, J.S.; Luo, R.; Feng, J.; Ye, S.; Yang, T.-S.; et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009, 10, 25–34. [Google Scholar] [CrossRef] [PubMed]
- Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; De Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A.; et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 2008, 359, 378–390. [Google Scholar] [CrossRef]
- Kudo, M.; Finn, R.S.; Qin, S.; Han, K.-H.; Ikeda, K.; Piscaglia, F.; Baron, A.; Park, J.-W.; Han, G.; Jassem, J.; et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet 2018, 391, 1163–1173. [Google Scholar] [CrossRef]
- Zheng, H.; Pomyen, Y.; Hernandez, M.O.; Li, C.; Livak, F.; Tang, W.; Dang, H.; Greten, T.F.; Davis, J.L.; Zhao, Y.; et al. Single-cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma. Hepatology 2018, 68, 127–140. [Google Scholar] [CrossRef]
- Chen, J.; Jin, R.; Zhao, J.; Liu, J.; Ying, H.; Yan, H.; Zhou, S.; Liang, Y.; Huang, D.; Liang, X.; et al. Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma. Cancer Lett. 2015, 367, 1–11. [Google Scholar] [CrossRef]
- Li, Y.; Laterra, J. Cancer stem cells: Distinct entities or dynamically regulated phenotypes? Cancer Res. 2012, 72, 576–580. [Google Scholar] [CrossRef]
- Zhou, G.; Latchoumanin, O.; Bagdesar, M.; Hebbard, L.; Duan, W.; Liddle, C.; George, J.; Qiao, L. Aptamer-based therapeutic approaches to target cancer stem cells. Theranostics 2017, 7, 3948–3961. [Google Scholar] [CrossRef]
- Bruix, J.; Qin, S.; Merle, P.; Granito, A.; Huang, Y.-H.; Bodoky, G.; Pracht, M.; Yokosuka, O.; Rosmorduc, O.; Breder, V.; et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017, 389, 56–66. [Google Scholar] [CrossRef]
- Abou-Alfa, G.K.; Meyer, T.; Cheng, A.-L.; El-Khoueiry, A.B.; Rimassa, L.; Ryoo, B.-Y.; Cicin, I.; Merle, P.; Park, J.-W.; Blanc, J.F.; et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. J. Clin. Oncol. 2018, 36, 207. [Google Scholar] [CrossRef]
- El-Khoueiry, A.B.; Sangro, B.; Yau, T.; Crocenzi, T.S.; Kudo, M.; Hsu, C.; Kim, T.-Y.; Choo, S.-P.; Trojan, J.; Welling, T.H.R., 3rd; et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017, 389, 2492–2502. [Google Scholar] [CrossRef] [PubMed]
- Singal, A.G.; Llovet, J.M.; Yarchoan, M.; Mehta, N.; Heimbach, J.K.; Dawson, L.A.; Jou, J.H.; Kulik, L.M.; Agopian, V.G.; Marrero, J.A.; et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 2023, 78, 1922–1965. [Google Scholar] [CrossRef] [PubMed]
- Wu, J.; Liu, W.; Qiu, X.; Li, J.; Song, K.; Shen, S.; Huo, L.; Chen, L.; Xu, M.; Wang, H.; et al. A noninvasive approach to evaluate tumor immune microenvironment and predict outcomes in hepatocellular carcinoma. Phenomics 2023, 3, 549–564. [Google Scholar] [CrossRef]
- Ho, H.K.; Pok, S.; Streit, S.; Ruhe, J.E.; Hart, S.; Lim, K.S.; Loo, H.L.; Aung, M.O.; Lim, S.G.; Ullrich, A. Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention. J. Hepatol. 2009, 50, 118–127. [Google Scholar] [CrossRef]
- Huynh, H.; Prawira, A.; Le, T.B.U.; Vu, T.C.; Hao, H.-X.; Huang, A.; Wang, Y.; Porta, D.G. FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma. Exp. Mol. Med. 2020, 52, 1857–1868. [Google Scholar] [CrossRef]
- Chen, Z.; Xie, B.; Zhu, Q.; Xia, Q.; Jiang, S.; Cao, R.; Shi, L.; Qi, D.; Li, X.; Cai, L. FGFR4 and TGF-β1 expression in hepatocellular carcinoma: Correlation with clinicopathological features and prognosis. Int. J. Med. Sci. 2013, 10, 1868–1875. [Google Scholar] [CrossRef]
- Desnoyers, L.R.; Pai, R.; Ferrando, R.E.; Hötzel, K.; Le, T.; Ross, J.; Carano, R.; D’Souza, A.; Qing, J.; Mohtashemi, I.; et al. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene 2008, 27, 85–97. [Google Scholar] [CrossRef]
- Hyeon, J.; Ahn, S.; Lee, J.J.; Song, D.H.; Park, C.-K. Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma. Dig. Dis. Sci. 2013, 58, 1916–1922. [Google Scholar] [CrossRef]
- Miura, S.; Mitsuhashi, N.; Shimizu, H.; Kimura, F.; Yoshidome, H.; Otsuka, M.; Kato, A.; Shida, T.; Okamura, D.; Miyazaki, M. Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer 2012, 12, 56. [Google Scholar] [CrossRef]
- Goetz, R.; Beenken, A.; Ibrahimi, O.A.; Kalinina, J.; Olsen, S.K.; Eliseenkova, A.V.; Xu, C.; Neubert, T.A.; Zhang, F.; Linhardt, R.J.; et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol. Cell Biol. 2007, 27, 3417–3428. [Google Scholar] [CrossRef]
- Katoh, M.; Nakagama, H. FGF receptors: Cancer biology and therapeutics. Med. Res. Rev. 2014, 34, 280–300. [Google Scholar] [CrossRef]
- Gauglhofer, C.; Paur, J.; Schrottmaier, W.C.; Wingelhofer, B.; Huber, D.; Naegelen, I.; Pirker, C.; Mohr, T.; Heinzle, C.; Holzmann, K.; et al. Fibroblast growth factor receptor 4: A putative key driver for the aggressive phenotype of hepatocellular carcinoma. Carcinogenesis 2014, 35, 2331–2338. [Google Scholar] [CrossRef]
- Zhou, M.; Wang, X.; Phung, V.; Lindhout, D.A.; Mondal, K.; Hsu, J.-Y.; Yang, H.; Humphrey, M.; Ding, X.; Arora, T.; et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res. 2014, 74, 3306–3316. [Google Scholar] [CrossRef]
- French, D.M.; Lin, B.C.; Wang, M.; Adams, C.; Shek, T.; Hötzel, K.; Bolon, B.; Ferrando, R.; Blackmore, C.; Schroeder, K.; et al. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS ONE 2012, 7, e36713. [Google Scholar] [CrossRef]
- Sawey, E.T.; Chanrion, M.; Cai, C.; Wu, G.; Zhang, J.; Zender, L.; Zhao, A.; Busuttil, R.W.; Yee, H.; Stein, L.; et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 2011, 19, 347–358. [Google Scholar] [CrossRef]
- Lin, B.C.; Desnoyers, L.R. FGF19 and cancer. Adv. Exp. Med. Biol. 2012, 728, 183–194. [Google Scholar] [CrossRef]
- Tai, D.W.M.; Le, T.B.U.; Prawira, A.; Ho, R.Z.W.; Huynh, H. Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma. Hepatol. Int. 2021, 15, 1236–1246. [Google Scholar] [CrossRef]
- Andreas, W.; Diana, G.P.; Flavia, R.; Alexandra, B.; Christelle, S.; Robin, A.F.; Jacqueline, K.-A.; Dario, S.; Masato, M.; Markus, W.; et al. Abstract 2103: NVP-FGF401: Cellular and in vivo profile of a novel highly potent and selective FGFR4 inhibitor for the treatment of FGF19/FGFR4/KLB+ tumors. Cancer Res. 2017, 77, 2103. [Google Scholar] [CrossRef]
- Chan, S.L.; Schuler, M.; Kang, Y.-K.; Yen, C.-J.; Edeline, J.; Choo, S.P.; Lin, C.-C.; Okusaka, T.; Weiss, K.-H.; Macarulla, T.; et al. A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors. J. Exp. Clin. Cancer Res. 2022, 41, 189. [Google Scholar] [CrossRef]
- Chan, S.L.; Yen, C.-J.; Schuler, M.; Lin, C.-C.; Choo, S.P.; Weiss, K.-H.; Geier, A.; Okusaka, T.; Lim, H.Y.; Macarulla, T.; et al. Abstract CT106: Ph I/II study of FGF401 in adult pts with HCC or solid tumors characterized by FGFR4/KLB expression. Cancer Res. 2017, 77, CT106. [Google Scholar] [CrossRef]
- Sahin, F.; Kannangai, R.; Adegbola, O.; Wang, J.; Su, G.; Torbenson, M. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin. Cancer Res. 2004, 10, 8421–8425. [Google Scholar] [CrossRef]
- Huynh, H.; Chow, P.K.; Palanisamy, N.; Salto-Tellez, M.; Goh, B.C.; Lee, C.K.; Somani, A.; Lee, H.S.; Kalpana, R.; Yu, K.; et al. Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J. Hepatol. 2008, 49, 52–60. [Google Scholar] [CrossRef]
- Zhou, L.; Huang, Y.; Li, J.; Wang, Z. The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med. Oncol. 2010, 27, 255–261. [Google Scholar] [CrossRef]
- Buitrago-Molina, L.E.; Vogel, A. mTor as a potential target for the prevention and treatment of hepatocellular carcinoma. Curr. Cancer Drug Targets 2012, 12, 1045–1061. [Google Scholar] [CrossRef]
- Chen, J.-S.; Wang, Q.; Fu, X.-H.; Huang, X.-H.; Chen, X.-L.; Cao, L.-Q.; Chen, L.-Z.; Tan, H.-X.; Li, W.; Bi, J.; et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9. Hepatol. Res. 2009, 39, 177–186. [Google Scholar] [CrossRef]
- Roberts, L.R.; Gores, G.J. Hepatocellular carcinoma: Molecular pathways and new therapeutic targets. Semin. Liver Dis. 2005, 25, 212–225. [Google Scholar] [CrossRef]
- Wang, Z.; Feng, X.; Molinolo, A.A.; Martin, D.; Vitale-Cross, L.; Nohata, N.; Ando, M.; Wahba, A.; Amornphimoltham, P.; Wu, X.; et al. 4E-BP1 Is a tumor suppressor protein reactivated by mTOR inhibition in head and neck cancer. Cancer Res. 2019, 79, 1438–1450. [Google Scholar] [CrossRef]
- Chiu, H.; Buono, R.; Jackson, L.V.; Herzog, L.-O.; Mallya, S.; Conn, C.S.; Ruggero, D.; Fruman, D.A. Reduced eIF4E function impairs B-cell leukemia without altering normal B-lymphocyte function. iScience 2021, 24, 102748. [Google Scholar] [CrossRef]
- Huynh, H.; Ng, W.H.; Soo, K.C. Everolimus acts in synergy with vinorelbine to suppress the growth of hepatocellular carcinoma. Int. J. Mol. Sci. 2023, 25, 17. [Google Scholar] [CrossRef]
- Mabuchi, S.; Altomare, D.A.; Cheung, M.; Zhang, L.; Poulikakos, P.I.; Hensley, H.H.; Schilder, R.J.; Ozols, R.F.; Testa, J.R. RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin. Cancer Res. 2007, 13, 4261–4270. [Google Scholar] [CrossRef]
- Mabuchi, S.; Altomare, D.A.; Connolly, D.C.; Klein-Szanto, A.; Litwin, S.; Hoelzle, M.K.; Hensley, H.H.; Hamilton, T.C.; Testa, J.R. RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Res. 2007, 67, 2408–2413. [Google Scholar] [CrossRef]
- Manegold, P.C.; Paringer, C.; Kulka, U.; Krimmel, K.; Eichhorn, M.E.; Wilkowski, R.; Jauch, K.-W.; Guba, M.; Bruns, C.J. Antiangiogenic therapy with mammalian target of rapamycin inhibitor RAD001 (Everolimus) increases radiosensitivity in solid cancer. Clin. Cancer Res. 2008, 14, 892–900. [Google Scholar] [CrossRef]
- Shinohara, E.T.; Cao, C.; Niermann, K.; Mu, Y.; Zeng, F.; Hallahan, D.E.; Lu, B. Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene. 2005, 24, 5414–5422. [Google Scholar] [CrossRef]
- Zhu, A.X.; Kudo, M.; Assenat, E.; Cattan, S.; Kang, Y.-K.; Lim, H.Y.; Poon, R.T.P.; Blanc, J.-F.; Vogel, A.; Chen, C.-L.; et al. EVOLVE-1: Phase 3 study of everolimus for advanced HCC that progressed during or after sorafenib. J. Clin. Oncol. 2014, 32, 172. [Google Scholar] [CrossRef]
- Semela, D.; Piguet, A.-C.; Kolev, M.; Schmitter, K.; Hlushchuk, R.; Djonov, V.; Stoupis, C.; Dufour, J.-F. Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J. Hepatol. 2007, 46, 840–848. [Google Scholar] [CrossRef]
- Sieghart, W.; Fuereder, T.; Schmid, K.; Cejka, D.; Werzowa, J.; Wrba, F.; Wang, X.; Gruber, D.; Rasoul-Rockenschaub, S.; Peck-Radosavljevic, M.; et al. Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation. Transplantation 2007, 83, 425–432. [Google Scholar] [CrossRef]
- Ribatti, D.; Nico, B.; Mangieri, D.; Longo, V.; Sansonno, D.; Vacca, A.; Dammacco, F. In vivo inhibition of human hepatocellular carcinoma related angiogenesis by vinblastine and rapamycin. Histol. Histopathol. 2007, 22, 285–289. [Google Scholar] [CrossRef]
- Zhou, Y.; Wu, C.; Lu, G.; Hu, Z.; Chen, Q.; Du, X. FGF/FGFR signaling pathway involved resistance in various cancer types. J. Cancer 2020, 11, 2000–2007. [Google Scholar] [CrossRef]
- National Research Council (US); Institute for Laboratory Animal Research (US). Guide for the Care and Use of Laboratory Animals; National Academies Press: Washington, DC, USA, 2011. [Google Scholar]
- Gabardi, S.; Baroletti, S.A. Everolimus: A proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology. Pharmacotherapy 2010, 30, 1044–1056. [Google Scholar] [CrossRef]
- Motzer, R.J.; Escudier, B.; Oudard, S.; Hutson, T.E.; Porta, C.; Bracarda, S.; Grünwald, V.; Thompson, J.A.; Figlin, R.A.; Hollaender, N.; et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: Final results and analysis of prognostic factors. Cancer 2010, 116, 4256–4265. [Google Scholar] [CrossRef]
- Zheng, S.; Chan, S.W.; Liu, F.; Liu, J.; Chow, P.K.H.; Toh, H.C.; Hong, W. Hepatocellular carcinoma: Current drug therapeutic status, advances and challenges. Cancers 2024, 16, 1582. [Google Scholar] [CrossRef]
- Hatlen, M.A.; Schmidt-Kittler, O.; Sherwin, C.A.; Rozsahegyi, E.; Rubin, N.; Sheets, M.P.; Kim, J.L.; Miduturu, C.; Bifulco, N.; Brooijmans, N.; et al. Acquired on-target clinical resistance validates FGFR4 as a driver of hepatocellular carcinoma. Cancer Discov. 2019, 9, 1686–1695. [Google Scholar] [CrossRef]
- Fearon, A.E.; Carter, E.P.; Clayton, N.S.; Wilkes, E.H.; Baker, A.-M.; Kapitonova, E.; Bakhouche, B.A.; Tanner, Y.; Wang, J.; Gadaleta, E.; et al. PHLDA1 mediates drug resistance in receptor tyrosine kinase-driven cancer. Cell Rep. 2018, 22, 2469–2481. [Google Scholar] [CrossRef]
- Lau, W.M.; Teng, E.; Huang, K.K.; Tan, J.W.; Das, K.; Zang, Z.; Chia, T.; Teh, M.; Kono, K.; Yong, W.P.; et al. Acquired resistance to FGFR inhibitor in diffuse-type gastric cancer through an AKT-independent PKC-mediated phosphorylation of GSK3β. Mol. Cancer Ther. 2018, 17, 232–242. [Google Scholar] [CrossRef]
- Llovet, J.M.; Villanueva, A.; Lachenmayer, A.; Finn, R.S. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat. Rev. Clin. Oncol. 2015, 12, 408–424. [Google Scholar] [CrossRef]
- Yang, Z.; Liang, S.-Q.; Yang, H.; Xu, D.; Bruggmann, R.; Gao, Y.; Deng, H.; Berezowska, S.; Hall, S.R.R.; Marti, T.M.; et al. CRISPR-mediated kinome editing prioritizes a synergistic combination therapy for FGFR1-amplified lung cancer. Cancer Res. 2021, 81, 3121–3133. [Google Scholar] [CrossRef]
- Moschetta, M.; Reale, A.; Marasco, C.; Vacca, A.; Carratù, M.R. Therapeutic targeting of the mTOR-signalling pathway in cancer: Benefits and limitations. Br. J. Pharmacol. 2014, 171, 3801–3813. [Google Scholar] [CrossRef]
- Huang, S.; Houghton, P.J. Targeting mTOR signaling for cancer therapy. Curr. Opin. Pharmacol. 2003, 3, 371–377. [Google Scholar] [CrossRef]
- Park, I.H.; Kong, S.-Y.; Kwon, Y.; Kim, M.K.; Sim, S.H.; Joo, J.; Lee, K.S. Phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple-negative breast cancer. J. Cancer 2018, 9, 1145–1151. [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. Invest. New Drugs 2019, 37, 559–566. [Google Scholar] [CrossRef]
- Taylor, S.E.; Chu, T.; Elvin, J.A.; Edwards, R.P.; Zorn, K.K. Phase II study of everolimus and bevacizumab in recurrent ovarian, peritoneal, and fallopian tube cancer. Gynecol. Oncol. 2020, 156, 32–37. [Google Scholar] [CrossRef]
- Grignani, G.; Palmerini, E.; Ferraresi, V.; D’Ambrosio, L.; Bertulli, R.; Asaftei, S.D.; Tamburini, A.; Pignochino, Y.; Sangiolo, D.; Marchesi, E.; et al. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: A non-randomised phase 2 clinical trial. Lancet Oncol. 2015, 16, 98–107. [Google Scholar] [CrossRef]
- Adib, E.; Klonowska, K.; Giannikou, K.; Do, K.T.; Pruitt-Thompson, S.; Bhushan, K.; Milstein, M.I.; Hedglin, J.; Kargus, K.E.; Sholl, L.M.; et al. Phase II clinical trial of everolimus in a pan-cancer cohort of patients with mTOR pathway alterations. Clin. Cancer Res. 2021, 27, 3845–3853. [Google Scholar] [CrossRef]
- Huynh, H.; Hao, H.-X.; Chan, S.L.; Chen, D.; Ong, R.; Soo, K.C.; Pochanard, P.; Yang, D.; Ruddy, D.; Liu, M.; et al. Loss of tuberous sclerosis complex 2 (TSC2) is frequent in hepatocellular carcinoma and predicts response to mTORC1 inhibitor everolimus. Mol. Cancer Ther. 2015, 14, 1224–1235. [Google Scholar] [CrossRef]
- Wan, X.; Harkavy, B.; Shen, N.; Grohar, P.; Helman, L.J. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 2007, 26, 1932–1940. [Google Scholar] [CrossRef]
- Lang, S.A.; Moser, C.; Fichnter-Feigl, S.; Schachtschneider, P.; Hellerbrand, C.; Schmitz, V.; Schlitt, H.J.; Geissler, E.K.; Stoeltzing, O. Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice. Hepatology 2009, 49, 523–532. [Google Scholar] [CrossRef]
- Huijts, C.M.; Santegoets, S.J.; de Jong, T.D.; Verheul, H.M.; de Gruijl, T.D.; van der Vliet, H.J. Immunological effects of everolimus in patients with metastatic renal cell cancer. Int. J. Immunopathol. Pharmacol. 2017, 30, 341–352. [Google Scholar] [CrossRef]
- Cao, R.; Ji, H.; Feng, N.; Zhang, Y.; Yang, X.; Andersson, P.; Sun, Y.; Tritsaris, K.; Hansen, A.J.; Dissing, S.; et al. Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proc. Natl. Acad. Sci. USA 2012, 109, 15894–15899. [Google Scholar] [CrossRef]
- Huynh, H.; Soo, K.C.; Chow, P.K.; Panasci, L.; Tran, E. Xenografts of human hepatocellular carcinoma: A useful model for testing drugs. Clin. Cancer Res. 2006, 12, 4306–4314. [Google Scholar] [CrossRef]
- Huynh, H.; Lee, L.Y.; Goh, K.Y.; Ong, R.; Hao, H.-X.; Huang, A.; Wang, Y.; Graus Porta, D.; Chow, P.; Chung, A. Infigratinib mediates vascular normalization, impairs metastasis, and improves chemotherapy in hepatocellular carcinoma. Hepatology 2019, 69, 943–958. [Google Scholar] [CrossRef] [PubMed]
Serum Marker | Unit | Vehicle | FGF401 30 mg/kg | Everolimus 1 mg/kg | FGF401/Everolimus |
---|---|---|---|---|---|
BUN | (mg/dL) | 14 ± 0.02 | 15 ± 0.97 | 14.5 ± 1.14 | 12.5 ± 1.08 |
CRE | (mg/dL) | 0.45 ± 0.05 | 0.2 ± 0.03 | 0.35 ± 0.029 | 0.2 ± 0.018 |
ALT | (U/L) | 38.5 ± 4.43 | 132 ± 15.10 * | 49.5 ± 5.62 | 140.5 ± 16.34 * |
ALP | (U/L) | 54 ± 7.12 | 66.5 ± 6.89 | 58 ± 6.11 | 73 ± 7.56 |
AST | (U/L) | 193 ± 18.30 | 368.5 ± 24.61 * | 249 ± 23.10 | 379 ± 32.6 * |
TBIL | (mg/dL) | 0.3 ± 0.014 | 0.3 ± 0.016 | 0.3 ± 0.011 | 0.3 ± 0.014 |
GLU | (mg/dL) | 162.5 ± 15.20 | 172 ± 14.23 | 136.5 ± 13.35 | 160 ± 13.71 |
ALB | (g/dL) | 4 ± 0.037 | 4.1 ± 0.032 | 3.7 ± 0.034 | 4.05 ± 0.029 |
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Huynh, H.; Ng, W.H. Reactivation of the PI3K/mTOR Signaling Pathway Confers Resistance to the FGFR4 Inhibitor FGF401. Int. J. Mol. Sci. 2025, 26, 9818. https://doi.org/10.3390/ijms26199818
Huynh H, Ng WH. Reactivation of the PI3K/mTOR Signaling Pathway Confers Resistance to the FGFR4 Inhibitor FGF401. International Journal of Molecular Sciences. 2025; 26(19):9818. https://doi.org/10.3390/ijms26199818
Chicago/Turabian StyleHuynh, Hung, and Wai Har Ng. 2025. "Reactivation of the PI3K/mTOR Signaling Pathway Confers Resistance to the FGFR4 Inhibitor FGF401" International Journal of Molecular Sciences 26, no. 19: 9818. https://doi.org/10.3390/ijms26199818
APA StyleHuynh, H., & Ng, W. H. (2025). Reactivation of the PI3K/mTOR Signaling Pathway Confers Resistance to the FGFR4 Inhibitor FGF401. International Journal of Molecular Sciences, 26(19), 9818. https://doi.org/10.3390/ijms26199818