Yusuf Zaidi

Background: Prostate cancer is a major global health concern.¹ Castration-resistant prostate cancer (CRPC) is an advanced subtype that poses a significant challenge due to its resistance to therapeutic interventions, with effective treatment options for CRPC being limited. Various risk factors, including age, genetics, and lifestyle factors, have been associated with the development of prostate cancer and CRPC.¹ The pathogenesis of CRPC involves androgen-dependent and androgen-independent growth signaling pathways, with alternative signaling pathways implicated in androgen-independent CRPC.² Screening and early detection are crucial for improved treatment outcomes, and treatment must be individualized to each patient’s unique stage and needs.¹ The current knowledge gap in the optimal therapeutic management of CRPC is the lack of effective therapeutics targeting the alternate signaling pathways commonly seen in the transition from prostate cancer to CRPC. Therefore, understanding and improving treatment options for CRPC is crucial in improving patient outcomes and quality of life.

Objective: The aim of this study was to conduct a thorough literature review of novel compounds targeting the PI3K/AKT/mTOR signaling pathway, which is frequently activated in patients with castration-resistant prostate cancer (CRPC).

Search Methods: A comprehensive search of the PubMed database was conducted using relevant keywords “castration-resistant prostate cancer,” “inhibitors,” and “PI3K/AKT/mTOR signaling pathway.” The search was limited to articles published in English within the last five years.

Results: The findings of the review suggest that the PI3K/AKT/mTOR pathway is an attractive target for treating CRPC. Anthopleura anjunae oligopeptide (AAP-H, YVPGP) was found to inhibit the PI3K/AKT/mTOR pathway, causing cell cycle stalling and apoptosis in DU-145 Pca cells without any toxic effect on NIH-3T3 cells.³ A combination of enzalutamide and lycopene was found to inhibit the progression and invasion of CRPC cells.⁴ Lycopene inhibited the expansion and metastatic spread of C4e2B and 22RV1 PCa cell lines, while supplementation of lycopene in the mouse model enhanced the inhibitory effect of enzalutamide.⁴ FGF21 was found to inhibit LNCaP cell proliferation, migration, and invasiveness, as well as increased LNCaP cell autophagy, indicating that FGF21 could be a viable candidate for future research in treating prostate cancer.⁵ MK2206 was found to inhibit Akt pathway activity and decrease cell movement and aerobic glycolysis in prostate cancer cells, while a combination of enzalutamide and AZD5363 was found to modulate the PI3K/AKT/mTOR signaling pathway and lead to anti-tumor activity in a Phase I trial for patients with resistant mCRPC.^6,7

Conclusion: The review explored novel compounds targeting the PI3K/AKT/mTOR signaling pathway in castration-resistant prostate cancer (CRPC). The findings suggest that targeting this pathway is a promising strategy for treating CRPC. Several compounds, including AAP-H, enzalutamide plus lycopene, FGF21, MK2206, and AZD5363 were found to inhibit CRPC cell proliferation, migration, and invasion. These results highlight the need for further research into novel compounds targeting the PI3K/AKT/mTOR pathway to improve treatment options for CRPC.

Works Cited:

1. Rebello RJ, Oing C, Knudsen KE, et al. Prostate cancer. Nat Rev Dis Primer. 2021;7(1):1-27. doi:10.1038/s41572-020-00243-0
2. Crowley F, Sterpi M, Buckley C, Margetich L, Handa S, Dovey Z. A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer. Res Rep Urol. 2021;13:457-472. doi:10.2147/RRU.S264722
3. Li X, Tang Y, Yu F, et al. Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway. Mar Drugs. 2018;16(9):325. doi:10.3390/md16090325
4. Chen X, Yang G, Liu M, et al. Lycopene enhances the sensitivity of castration-resistant prostate cancer to enzalutamide through the AKT/EZH2/ androgen receptor signaling pathway. Biochem Biophys Res Commun. 2022;613:53-60. doi:10.1016/j.bbrc.2022.04.126
5. Dai H, Hu W, Zhang L, et al. FGF21 facilitates autophagy in prostate cancer cells by inhibiting the PI3K–Akt–mTOR signaling pathway. Cell Death Dis. 2021;12(4):303. doi:10.1038/s41419-021-03588-w
6. Tee SS, Suster I, Truong S, et al. Targeted AKT Inhibition in Prostate Cancer Cells and Spheroids Reduces Aerobic Glycolysis and Generation of Hyperpolarized [1-13C] Lactate. Mol Cancer Res MCR. 2018;16(3):453-460. doi:10.1158/1541-7786.MCR-17-0458
7. Kolinsky MP, Rescigno P, Bianchini D, et al. A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer. Ann Oncol Off J Eur Soc Med Oncol. 2020;31(5):619-625. doi:10.1016/j.annonc.2020.01.074