The Role of PI3K/AKT/mTOR Signaling in Tumor Radioresistance and Advances in Inhibitor Research
Abstract
1. Introduction
2. The Role of the PI3K/AKT/mTOR Pathway in Tumor Radioresistance
2.1. DNA Damage Repair
2.2. Cell Cycle
2.3. Cell Proliferation and Apoptosis
2.4. Cell Invasion and Metastasis
2.5. Autophagy and Hypoxia
2.6. Cancer Stem Cells
3. The Impact of Different PI3K/AKT/mTOR Isoforms on Radioresistance
3.1. PI3K Isoforms
3.2. AKT Isoforms
3.3. mTOR Isoforms
4. Preclinical Studies of PI3K/AKT/mTOR Inhibitors Combined with Radiotherapy
4.1. Digestive System Tumors
4.2. Genitourinary System Tumors
4.3. Respiratory System Tumors
4.4. Breast Cancer
4.5. Central Nervous System Tumors
5. Clinical Studies on PI3K/AKT/mTOR Inhibitors Combined with Radiotherapy
6. Future Research Directions
6.1. Molecular Design and the Targeted Optimization of Novel Inhibitors
6.2. Combination Therapy Strategies
6.3. Identification of Predictive Tumor Biomarkers
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
4E-BP1 | Eukaryotic translation initiation factor 4E-binding protein 1 |
53BP1 | p53-binding protein 1 |
A2aR | Adenosine A2a receptor |
AKT | Protein kinase B |
ANXA6 | Annexin A6 |
APLNR | Apelin receptor |
ATG5 | Autophagy-related gene 5 |
ATM | Ataxia telangiectasia mutated |
ATR | Ataxia telangiectasia and Rad3-related |
BABAM1 | BRISC and BRCA1-A complex member 1 |
BAD | Bcl-2-associated agonist of cell death |
Bax | Bcl-2-associated X protein |
Bcl-2 | B-cell lymphoma 2 |
C2orf40 | Chromosome 2 open reading frame 40 |
CALD1 | Caldesmon 1 |
CD44 | Cluster of differentiation 44 |
CDK1 | Cyclin-dependent kinase 1 |
Chk2 | Checkpoint kinase 2 |
c-Jun | Cellular Jun proto-oncogene |
CRC | Colorectal cancer |
CSCs | Cancer stem cells |
DDRs | DNA damage responses |
DEPTOR | DEP domain-containing mTOR-interacting protein |
DNA-PKcs | DNA-dependent protein kinase catalytic subunit |
DSBs | DNA double-strand breaks |
EMT | Epithelial–mesenchymal transition |
EpCAM | Epithelial cell adhesion molecule |
ESCC | Esophageal squamous cell carcinoma |
FA | Fanconi anemia |
FAM135B | Family with sequence similarity 135, member B |
FANCD2 | Fanconi anemia complementation group D2 |
FOXO1 | Forkhead Box O1 |
GBM | Glioblastoma |
Glut-1 | Glucose transporter 1 |
GSK-3β | Glycogen synthase kinase 3 beta |
GβL | G-protein β-subunit-like protein |
HIF-1α | Hypoxia-inducible factor 1-alpha |
HNSCC | Head and neck squamous cell carcinoma |
HR | Homologous recombination |
Hsp90 | Heat shock protein 90 |
IMRT | Intensity-modulated radiotherapy |
LC3-II | Microtubule-associated protein 1 light chain 3 II |
MDSC | Myeloid-derived suppressor cell |
mLST8 | Mammalian lethal with SEC13 protein 8 |
MRN | MRE11-RAD50-NBS1 complex |
mTOR | Mammalian target of rapamycin |
Nbs1 | Nijmegen breakage syndrome 1 protein |
NEDD8 | Neural precursor cell expressed, developmentally downregulated 8 |
NHEJ | Non-homologous end joining |
NPC | Nasopharyngeal carcinoma |
NSCLC | Non-small-cell lung cancer |
OCT-4 | Octamer-binding transcription factor 4 |
OS | Overall survival |
P62 | Sequestosome-1 |
PARP1 | Poly(ADP-ribose)polymerase 1 |
PCNA | Proliferating cell nuclear antigen |
PDK1 | Phosphoinositide-dependent protein kinase 1 |
PFS | Progression-free survival |
PI3K | Phosphatidylinositol 3-Kinase |
PRAS40 | Proline-rich AKT substrate of 40 kDa |
PTEN | Phosphatase and tensin homolog |
RAPTOR | Regulatory-associated protein of mTOR |
Rad51 | RAD51 recombinase |
Rb | Retinoblastoma protein |
RCC | Renal cell carcinoma |
RFC1 | Replication factor C subunit 1 |
RNR | Phosphorylates ribonucleotide reductase |
ROS | Reactive oxygen species |
S2056 | Serine 2056 |
S6K | Sibosomal protein S6 kinase |
SBRT | Stereotactic body radiotherapy |
SCLC | Small-cell lung cancer |
SIN1 | Stress-activated protein kinase-interacting protein 1 |
SIRT6 | Sirtuin 6 |
SLC7A5 | Solute carrier family 7 member A5 |
SMA | Smooth muscle actin |
SOX2 | SRY-box transcription factor 2 |
SSBs | Single-strand breaks |
TAMs | Tumor-associated macrophages |
TEH | Tenacissoside H |
VEGF | Vascular endothelial growth factor |
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Inhibitor | Target | Population | Experimental Model | Radiotherapy Dose | Summary Outcome |
---|---|---|---|---|---|
Alpelisib | PI3K | Cervical cancer | In vivo (patient-derived orthotopic cervical cancer xenograft model) | 2 Gy × 15 | Combination therapy significantly reduced tumor volume in tumor model. |
GDC0032 (Taselisib) | PI3K | Non-small-cell lung cancer | In vitro (cell lines: A549, LLC1) In vivo (LLC1 xenograft model) | In vitro: 2, 4, 6 Gy In vivo: 5 Gy × 1 | It could significantly reduce the cell cloning rate, decrease radioresistance, and delay tumor growth in tumor models. |
PI3K | Glioblastoma | In vitro (cell lines: LN229, GL261-luc) In vivo (GL261-luc intracranial xenograft model) | In vitro: 1, 2, 3, 4, 6 Gy In vivo: 2 Gy × 5 | Combined radiotherapy significantly reduced the cloning rate of GBM cells and decreased radioresistance. | |
CAL101 (Idelalisib) | PI3K | Glioblastoma | In vitro (LN229, GL261-luc) | 1, 2 Gy | Combined radiotherapy could decrease radioresistance. |
IPI145 (Duvelisib) | PI3K | Glioblastoma | In vitro (LN229, GL261-luc) | 1, 2 Gy | Combined radiotherapy was more effective than radiotherapy alone. |
GDC0941 (Pictilisib) | PI3K | Glioblastoma | In vitro (LN229, GL261-luc) | 1, 2, 3, 4, 6 Gy | Combined radiotherapy could reduce the cell survival fraction. |
BKM120 (Buparlisib) | PI3K | Head and neck squamous cell carcinoma | In vitro (cell lines: SCC154, SCC104, SCC47 (HPV+); SQD9, SCC61, CAL27 (HPV−)) | 0, 2, 4, 6 Gy | Only weak radiosensitization was observed in the HPV+ cell line SCC154, and most cell lines had no obvious synergistic effect. |
GSK2126458 | PI3K/mTOR | Small-cell lung cancer | In vitro (cell lines: SBC2, H446, DMS53, H446RR) In vivo (mouse model and subcutaneous allografts) | In vitro: 2, 4, 6 Gy In vivo: 6 Gy × 4 | Significantly decreased the radioresistance of SCLC cells, including inhibiting proliferation, increasing apoptosis, and reducing tumor volume and weight. |
NVP-BEZ235 | PI3K/mTOR | Colorectal cancer | In vitro (cell lines: HCT116, HT29, SW480) In vivo (HCT116 xenograft tumor model) | In vitro: 1, 2, 3, 5 Gy In vivo: 2 Gy × 3 | Significantly inhibited colorectal cancer cell viability, increased cell apoptosis, and significantly reduced tumor volume in xenograft models. |
PI3K/mTOR | Prostate cancer | In vitro (cell line: PC-3) | 2, 4, 6, 8, 10 Gy | Pretreatment significantly decreased the radioresistance of PC-3 cells in a dose-dependent manner. | |
PI3K/mTOR | Breast cancer | In vitro (MCF-7 cells) | 2 Gy | Reduced cell viability and decreased radioresistance. | |
PF-04691502 | PI3K/mTOR | Gastroenteropancreatic neuroendocrine tumors | In vitro (cell lines: QGP-1, BON, NT-3) | 2, 4, 8 Gy | Use after radiotherapy could significantly increase cell apoptosis and show anti-proliferative effects. |
PI-103 | PI3K/mTOR | Glioblastoma | In vitro (cell lines: MO59K, MO59J) | 0, 2, 3, 5, 6, 8 Gy | Radiosensitization effect on MO59K cells. |
PKI-402 | PI3K/mTOR | Breast cancer | In vitro (cell lines: MCF-7, MDA-MB-231, BCSCs, MCF-10A) | 0, 2, 4, 6, 8, 10 Gy | Inhibited the colony formation of MCF-7 and BCSC and increased the apoptosis of MCF-7. |
PKI-587 | PI3K/mTOR | Hepatocellular carcinoma | In vitro (cell line: SK-Hep1) In vivo (SK-Hep1 xenograft model) | In vitro: 0, 2, 4, 6, 8 Gy In vivo: 2 Gy × 4 | Significantly decreased the radioresistance of liver cancer cells and significantly inhibited tumor growth in xenograft models. |
GDC-0068 (Ipatasertib) | AKT | Triple-negative breast cancer | In vitro (cell line: MDA-MB-231BR; parental line: MDA-MB-231) | 0, 2, 4, 6 Gy | Significantly reduced cell viability at high concentrations (20 μM) and decreased radioresistance at IC20 concentrations (6 μM). |
MK-2206 | AKT | Triple-negative breast cancer | In vitro (MDA-MB-231) | 4 Gy | Administration of 10 μM MK-2206 48 h after radiotherapy reduced Akt1 expression and synergistically enhanced radiotherapy-induced apoptosis. |
AKT | Glioblastoma | In vitro (cell lines: DK-MG, SNB19) | 0, 2, 3, 5, 7, 8 Gy | Increased the radioresistance of SNB19 cells. | |
Everolimus | mTOR | Renal cell carcinoma | In vitro (cell lines: 786-O, Renca) In vivo (subcutaneous and orthotopic Renca xenografts, 786-O xenografts) | In vitro: 2 Gy In vivo: 10 Gy × 2 | Everolimus could enhance the sensitivity of renal cell carcinoma to radiation. |
mTOR | Bladder cancer | In vitro (cell lines: UM-UC3, UM-UC5, UM-UC6, KU7, 253J-BV, 253-JP) In vivo (KU7 and 253J-BV xenograft models) | In vitro: 0, 1, 2, 3, 4 Gy In vivo: 3 Gy × 3 | The combination therapy significantly reduced the colony formation rate of bladder cancer cells, showing an additive effect. | |
INK128 | mTOR | Pancreatic carcinoma | In vitro (cell lines: PSN1, Panc1, Miapaca-2) In vivo (PSN1 xenograft model) | In vitro: 0, 2, 4, 6, 8 Gy In vivo: 6 Gy, 2 Gy × 4 | Decreased radioresistance of pancreatic cancer cells. |
Temsirolimus | mTOR | Colorectal cancer | In vitro (cell lines): HT-29, SW480 | 0, 2, 4, 6 Gy | The combination of temsirolimus and chloroquine decreased the radioresistance of CRC cells by co-inhibiting mTOR and autophagy. |
mTOR | Non-small-cell lung cancer | In vitro (cell lines: A549, NCI-H460) In vivo (A549 xenograft model) | In vitro: 0, 2, 4, 6, 8 Gy In vivo: 2 Gy × 4 | It reduced the colony formation rate of cancer cells and enhanced radiation-induced apoptosis, reducing tumor volume in in vivo models. | |
mTOR | Nasopharyngeal carcinoma | In vitro (cell lines: 5-8F, HNE-1, C666-1, 6-10B, CNE-2; radio-resistant cell line: C666-1-r) In vivo (C666-1-r xenograft model) | In vitro: 0, 2.5, 5, 10, 20, 40 Gy In vivo: no mention | It could significantly decrease the radioresistance of nasopharyngeal carcinoma cells. In xenograft models, temsirolimus reduced the tumor formation rate in a dose-dependent manner. | |
Sapanisertib | mTOR | Head and neck squamous cell carcinoma | In vitro (cell lines: CAL33 (HPV−), UD-SCC-2 (HPV+), UM-SCC-47 (HPV+), HSC4 (HPV−); normal cells: SBLF7/SBLF9 fibroblasts, HaCaT keratinocytes) | 2 Gy | Combination with radiotherapy increased cell death and G2/M arrest and reduced clonogenicity. |
Inhibitor | Target | Population | Phase | ClinicalTrials.Gov Identifier |
---|---|---|---|---|
Alpelisib | PI3K | Head and Neck Squamous Cell Cancer | 1 | NCT02282371 Start date: October 2014 Completion date: October 2021 |
PI3K | Head and Neck Cancer | 1 | NCT02537223 Start date: September 2015 Completion date: February 2020 | |
Buparlisib | PI3K | Carcinoma, Non-Small-Cell Lung | 1 | NCT02128724 Start date: April 2013 Completion date: October 2017 |
PI3K | Head and Neck Cancer | 1 | NCT02113878 Start date: September 2014 Completion date: January 2022 | |
PI3K | Glioblastoma | 1 | NCT01473901 Start date: December 2011 Completion date: May 2017 | |
Voxtalisib | PI3K/mTOR | Glioblastoma | 1 | NCT00704080 Start date: August 2008 Completion date: February 2013 |
Paxalisib | PI3K/mTOR | Brain Metastases | 1 | NCT04192981 Start date: December 2019 Completion date: December 2025 |
PI3K/mTOR | Diffuse Midline Gliomas | 2 | NCT05009992 Start date: October 2021 Completion date: June 2029 | |
PI3K/mTOR | Glioblastoma | 2/3 | NCT03970447 Start date: July 2019 Completion date: June 2028 | |
Capivasertib | AKT | Breast Cancer | 2 | NCT06607757 Start date: December 2024 Completion date: August 2026 |
Ipatasertib | AKT | Head and Neck Cancer | 1 | NCT05172245 Start date: September 2022 Completion date: June 2026 |
Nelfinavir | AKT | Glioblastoma | 1 | NCT00694837 Start date: March 2009 Completion date: January 2013 |
AKT | Oligometastases | 2 | NCT01728779 Start date: January 2014 Completion date: December 2020 | |
AKT | Cervical Cancer | 1 | NCT01485731 Start date: January 2012 Completion date: February 2015 | |
AKT | Pancreatic Cancer | 1 | NCT01068327 Start date: November 2007 Completion date: February 2015 | |
AKT | Pancreatic Cancer | 2 | NCT01959672 Start date: September 2013 Completion date: December 2018 | |
AKT | Glioblastoma | 1 | NCT01020292 Start date: April 2009 Completion date: December 2017 | |
AKT | Non-Small-Cell Lung Cancer | 1/2 | NCT00589056 Start date: June 2007 Completion date: March 2012 | |
AKT | Pancreatic Cancer | 1/2 | NCT00589056 Start date: March 2016 Completion date: June 2021 | |
AKT | Cervical Cancer | 1 | NCT02363829 Start date: February 2015 Completion date: February 2020 | |
AKT | Head and Neck Squamous Cell Cancer | 2 | NCT02207439 Start date: July 2014 Completion date: May 2022 | |
Everolimus | mTOR | High-Grade Glioma | 2 | NCT05843253 Start date: August 2024 Completion date: August 2034 |
mTOR | Neuroendocrine Tumors | 3 | NCT05918302 Start date: October 2023 Completion date: July 2028 | |
mTOR | Diffuse Intrinsic Pontine Glioma | 3 | NCT05476939 Start date: September 2022 Completion date: September 2031 | |
mTOR | Glioblastoma | 1/2 | NCT00553150 Start date: March 2009 Completion date: November 2019 | |
mTOR | Head and Neck Cancer | 1 | NCT00858663 Start date: March 2009 Completion date: July 2013 | |
mTOR | Glioblastoma | 1/2 | NCT01062399 Start date: December 2010 Completion date: May 2022 | |
mTOR | Cervix Cancer | 1 | NCT01217177 Start date: December 2011 Completion date: April 2014 | |
Temsirolimus | mTOR | Rhabdomyosarcoma | 3 | NCT02567435 Start date: June 2016 Completion date: October 2025 |
mTOR | Diffuse Intrinsic Pontine Glioma | 1 | NCT02420613 Start date: October 2015 Completion date: October 2024 | |
mTOR | Non-Small-Cell Lung Cancer | 1 | NCT00796796 Start date: March 2009 Completion date: July 2011 | |
mTOR | Glioblastoma | 1 | NCT00316849 Start date: May 2006 Completion date: November 2010 | |
mTOR | Glioblastoma | 2 | NCT01019434 Start date: October 2009 Completion date: March 2014 |
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Zhan, J.; Jücker, M. The Role of PI3K/AKT/mTOR Signaling in Tumor Radioresistance and Advances in Inhibitor Research. Int. J. Mol. Sci. 2025, 26, 6853. https://doi.org/10.3390/ijms26146853
Zhan J, Jücker M. The Role of PI3K/AKT/mTOR Signaling in Tumor Radioresistance and Advances in Inhibitor Research. International Journal of Molecular Sciences. 2025; 26(14):6853. https://doi.org/10.3390/ijms26146853
Chicago/Turabian StyleZhan, Jian, and Manfred Jücker. 2025. "The Role of PI3K/AKT/mTOR Signaling in Tumor Radioresistance and Advances in Inhibitor Research" International Journal of Molecular Sciences 26, no. 14: 6853. https://doi.org/10.3390/ijms26146853
APA StyleZhan, J., & Jücker, M. (2025). The Role of PI3K/AKT/mTOR Signaling in Tumor Radioresistance and Advances in Inhibitor Research. International Journal of Molecular Sciences, 26(14), 6853. https://doi.org/10.3390/ijms26146853