Volume : 13, Issue : 05, May – 2026

Title:

TARGETING THE PI3K/AKT/MTOR PATHWAY IN PROSTATE CANCER: OVERCOMING RESISTANCE VIA COMBINATION STRATEGIES

Authors :

Fathima Rasma K*, Dr. Vivek D, Dr. Shahin Muhammed TK, Deepika PK*

Abstract :

Prostate cancer remains a leading malignancy in men worldwide, with aberrant activation of the PI3K/AKT/mTOR signaling pathway recognized as a central driver of disease progression and therapeutic resistance. Loss of PTEN and recurrent mutations in PIK3CA, AKT, and mTOR sustain oncogenic signaling, promoting castration-resistant prostate cancer (CRPC). The pathway’s reciprocal crosstalk with androgen receptor (AR), MAPK, and WNT signaling underscores its role at the crossroads of multiple oncogenic networks, complicating monotherapy approaches. A wide spectrum of inhibitors—including pan-PI3K, isoform-selective PI3K, AKT, mTOR, and dual PI3K/mTOR agents—have demonstrated biological activity, yet clinical outcomes remain modest due to compensatory signaling and toxicity. Emerging strategies emphasize rational combination therapies, particularly with AR blockade, PARP inhibitors, immune checkpoint inhibitors, and chemotherapy, to enhance efficacy and overcome resistance. Novel dual-targeted agents such as PI3K/HDAC inhibitors further highlight the potential of multipathway inhibition in biomarker-defined patient populations. Collectively, these advances position PI3K-targeted therapies as a cornerstone of next-generation prostate cancer management, offering promise for durable outcomes in CRPC.
Key words :PI3K, AKT, mTOR, PTEN, Resistance

Cite This Article:

Please cite this article in press Fathima Rasma K et al., Targeting The Pi3k/Akt/Mtor Pathway In Prostate Cancer: Overcoming Resistance Via Combination Strategies.., Indo Am. J. P. Sci, 2026; 13(05).

REFERENCES:

1. International Agency for Research on Cancer. Prostate cancer [Internet]. Lyon (FR): World Health Organization, International Agency for Research on Cancer; 2024 [cited 2026 Feb 23]. Available from: https://www.iarc.who.int/cancer-types/prostate-cancer
2. Rawla P. Epidemiology of prostate cancer. World J Oncol. 2019;10(2):63-89
3. Sankarapillai J, Krishnan S, Ramamoorthy T, Sudarshan KRL, Mathur P. Descriptive epidemiology of prostate cancer in India, 2012–2019: Insights from the National Cancer Registry Programme. Indian J Urol. 2021;37(2):167–173. doi: 10.4103/iju.IJU _282_20.
4. Litwin MS, Tan HJ. The diagnosis and treatment of prostate cancer: A review. JAMA. 2017 Jun 27;317(24):2532-2542. doi:10.1001/jama.2017.7248
5. Morgan TM, Koreckij TD, Corey E. Targeted therapy for advanced prostate cancer: Inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets. 2009 Mar;9(2):237–249
6. Yang J, Zhao Y, Li J, Zhang Y, Wang L, Xu J. Pyrazolo[3,4-d]pyrimidine derivatives as targeted anticancer agents: synthesis, biological evaluation, and mechanism of action. Eur J Med Chem. 2017;138:66 80. doi:10.1016/j.ejmech.2017.06.045
7. Cai F,Zhao Y, Yang L, Wang J, Qian W, Zhang G, et al. Role of phosphatidylinositol-3-kinase /protein kinase B signaling in androgen-independent prostate cancer progression. Adv Radiother Nucl Med. 2025;3(3):34-42. doi:10.36922/ARNM025160018.
8. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: Divergent roles of isoforms, modes of activation and therapeutic strategies. Nat Rev Cancer. 2015;15(1):7 24. doi:10.1038/nrc3860.
9. Shorning BY, Dass MS, Smalley MJ, Pearson HB. The PI3K–AKT–mTOR pathway and prostate cancer: At the crossroads of AR, MAPK, and WNT signaling. Int J Mol Sci. 2020;21(22):7980. doi:10.3390/ijms21227980.
10. Tortorella E, Giantulli S, Sciarra A, Silvestri I. AR and PI3K/AKT in prostate cancer: a tale of two interconnected pathways.Int J Mol Int J Mol Sci. 2023;24(3):2046. doi:10.3390/ijms24032046.
11. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN deficient prostat prostate cancer. Cancer Cell. 2011;19(5):575 86. doi:10.1016/j.ccr.2011.04.008.
12. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Ipatasertib plus abiraterone for metastatic castration resistant prostate cancer (IPATential150): A randomized, double blind, phase 3 trial.Lancet. 2020;398(10295):131-142. doi:10.1016/S0140 6736(20)31960 X.
13. Son B, Lee W, Kim H, Shin H, Park HH. Targeted therapy of cancer stem cells: inhibition of mTOR in pre clinical and clinical research. Cell Death Dis. 2024;15:696. doi:10.1038/s41419 024 07077 8.
14. Hashemi M, Yousefi B, Rezaei F, Iranshahi M. Targeting PI3K/Akt signaling in prostate cancer therapy. Cell Mol Biol Lett. 2022;27:74. doi:10.1186/s11658-022-00373-9.
15. Alobid S. Targeting the PI3K/AKT/mTOR signaling pathway in prostate cancer: Molecular dysregulation, therapeutic advances, and future directions. Saudi Pharm J. 2026;34(2):1 17. doi:10.1007/s44446 025 00056 w
16. Ruiz de Porras V, Bernat Peguera A, Alcon C, Laguia F, Fernández Saorin M, Jiménez N, et al. Dual inhibition of MEK and PI3Kβ/δ – a potential therapeutic strategy in PTEN wild type docetaxel resistant metastatic prostate cancer. Front Pharmacol. 2024;15:1331648. doi:10.3389/fphar.2024.1331648.
17. Subbiah V, Coleman N, Piha Paul SA, Tsimberidou AM, Janku F, Rodon J, Pant S, Dumbrava EEI, Fu S, Hong DS, Zhang S, Sun M, Jiang Y, Roszik J, Song J, Yuan Y, Meric Bernstam F, Naing A. Phase I study of mTORC1/2 inhibitor sapanisertib (CB 228/TAK 228) in combination with metformin in patients with mTOR/AKT/PI3K pathway alterations and advanced solid malignancies. Cancer Res Commun. 2024;4(2):378 388. doi:10.1158/2767 9764.CRC 22 0260.
18. Sugawara T, Nevedomskaya E, Heller S, Böhme A, Lesche R, von Ahsen O, et al. Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis. Molecular Oncology. 2024;18(3):726–742. doi:10.1002/1878-0261.13577.
19. Alobid S. Targeting the PI3K/AKT/mTOR signaling pathway in prostate cancer: molecular dysregulation, therapeutic advances, and future directions. Saudi Pharm J. 2026;34(2):1 17. doi:10.1007/s44446 025 00056 w.
20. Guo R, Shi L, Chen Y, Lin C, Yin W. Exploring the roles of ncRNAs in prostate cancer via the PI3K/AKT/mTOR signaling pathway. Front Immunol. 2025;16:1525741. doi:10.3389/fimmu.2025.1525741.