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. 2024 Oct;84(14):1301-1308.
doi: 10.1002/pros.24765. Epub 2024 Jul 17.

PIK3/Akt/mTOR pathway alterations in metastatic castration-sensitive prostate cancer

Philip Sutera  1 , Jongmyung Kim  2 , Ritesh Kumar  2 , Rebecca A Deek  3 , Ryan Stephenson  4 , Tina Mayer  4 , Biren Saraiya  4 , Saum Ghodoussipour  5 , Thomas Jang  5 , David Golombos  5 , Vignesh Packiam  5 , Ronald Ennis  1 , Lara Hathout  1 , Salma K Jabbour  1 , Ozan Guler  6 , Cem Onal  6 , Phuoc T Tran  7 , Matthew P Deek  1
Affiliations

PIK3/Akt/mTOR pathway alterations in metastatic castration-sensitive prostate cancer

Philip Sutera et al. Prostate. 2024 Oct.

Abstract

Background: Alterations in the PIK3/Akt/mTOR pathway are commonly seen in metastatic castration-sensitive prostate cancer (mCSPC), however their role in outcomes is unknown. We aim to evaluate the prognostic significance as well as the genetic landscape of PIK3/Akt/mTOR pathway alteration in mCSPC.

Methods: Fourhundred and seventy-two patients with mCSPC were included who underwent next generation sequencing. PIK3/Akt/mTor pathway alterations were defined as mutations in Akt1, mTOR, PIK3CA, PIK3CB, PIK3R1, PTEN, TSC1, and TSC2. Endpoints of interests were radiographic progression-free survival (rPFS), time to development of castration resistant prostate cancer (tdCRPC), and overall survival (OS). Kaplan-Meier analysis was performed and Cox regression hazard ratios (HR) were calculated.

Results: One hundred and fifty-two (31.9%) patients harbored a PIK3/Akt/mTOR pathway alteration. Median rPFS and tdCRPC were 23.7 and 21.0 months in PIK3/Akt/mTOR altered compared to 32.8 (p = 0.08) and 32.1 months (p = 0.002) in wildtype tumors. On multivariable analysis PIK3/Akt/mTOR pathway alterations were associated with tdCRPC (HR 1.43, 95% CI, 1.05-1.94, p = 0.02), but not rPFS [Hazard ratio (HR) 1.20, 95% confidence interval (CI), 0.90-1.60, p = 0.21]. PIK3/Akt/mTOR pathway alterations were more likely to be associated with concurrent mutations in TP53 (40% vs. 28%, p = 0.01) and TMPRSS2-ERG (37% vs. 26%, p = 0.02) than tumors without PIK3/Akt/mTOR pathway alterations. Concurrent mutations were typically associated with shorter median times to rPFS and tdCRPC. DAVID analysis showed p53 signaling and angiogenesis pathways were enriched in PIK3/Akt/mTOR pathway altered tumors while beta-catenin binding and altered BRCA pathway were enriched in PIK3/Akt/mTOR pathway wildtype tumors.

Conclusions: PIK3/Akt/mTOR pathway alterations were common in mCSPC and associated with poorer prognosis. The genetic landscape of PIK3/Akt/mTOR pathway altered tumors differed from wildtype tumors. Additional studies are needed to better understand and target the PIK3/Akt/mTOR pathway in mCSPC.

Keywords: PIK3; genomics; personalized medicine; prostate cancer.

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References

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