Abstract 2498: Identification and characterization of the <i>PIK3R1</i>-mutant subtype in PI3K-addicted prostate cancer
Authors: Goutam Chakraborty, Subhiksha Nandakumar, Rahim Hirani, Sai Harisha Rajanala, Bastien Nguyen, Romina Ghale, Ying Z. Mazzu, Lina E. Jehane, Gwo-Shu Mary Lee, Lorelei A. Mucci, Nikolaus Schultz, Philip W. Kantoff
Journal: Cancer Research (2021)

Abstract Metastatic castration-resistant metastatic prostate cancer (mCRPC) is incurable. Recent comprehensive genomic characterization of localized and metastatic prostate cancer has identified a long tail of oncogenic driver mutations and demonstrated recurrent alteration of genes involved in phosphoinositide 3-kinase (PI3K) signaling in ~40% mCRPC cases. Alterations in the PI3K-signaling pathway in cancer have led to a surge in the development of PI3K/Akt inhibitors and many of these targeted therapies are currently in clinical trials and show great promise for the treatment of PI3K-addicted tumors. Therefore, in precision oncology, the identification of advanced prostate cancers with high PI3K activity is critical for treatment selection and eligibility into clinical trials of PI3K/Akt inhibitors. We analyzed panel sequencing data from 2965 prostate cancer patients (1770 localized and 1195 mCRPC cases) from the Memorial Sloan Kettering Cancer Center clinical sequencing cohort (MSK-IMPACT). The MSK-IMPACT panel sequencing includes all protein-coding mutations, copy number alterations, selected promoter mutations and structural rearrangements of 341, 410 and 468 cancer-associated genes (all panels included). Among the PI3K-AKT-mTOR pathway components (19 genes in MSK-IMPACT panel) we identified a significant enrichment of PIK3R1 (regulatory subunit that codes for p85α protein and modulates the catalytic activity of PI3K-pathway) alterations in mCRPC patients compared to localized prostate cancer (5% mCRPC vs 2% localized cases; p&amp;lt;0.0001). Copy number analysis identified more frequent deletion of the PIK3R1 chromosomal region in mCRPC compared to localized disease (Chromosome 5q13.1; 25% vs 15% p&amp;lt; 0.0001). We also observed that loss of PIK3R1 mRNA is associated with shorter biochemical recurrence-free survival of patients in primary prostate cancer cohorts (low vs high quartile; TCGA; HR: 2.8 and Taylor et al, HR: 2.6) indicating that PIK3R1 inactivation may act as a driver of aggressive prostate cancer. Experimentally we showed that RNAi mediated knockdown of PIK3R1 was sufficient to induce Akt-activation and increase cell growth in human prostate cancer cell line (LAPC4 and 22RV1) models. Most importantly we showed that Akt-inhibitors ipatasertib and MS2206 strongly reduced the viability of prostate cancer cells (LAPC4 and 22RV1) with PIK3R1 knockdown or PIK3R1 mutated mCRPC derived organoid (MSKPCa3) compared to PIK3R1 wild type cells irrespective of their PTEN status. In summary, our study identified an association between PIK3R1 alterations and lethal prostate cancer and demonstrated that men with mCRPC who harbor defective PIK3R1 may benefit from Akt inhibitors. Further in-depth studies are warranted to uncover the biological and phenotypic characterization of PIK3R1-altered prostate cancer. Citation Format: Goutam Chakraborty, Subhiksha Nandakumar, Rahim Hirani, Sai Harisha Rajanala, Bastien Nguyen, Romina Ghale, Ying Z. Mazzu, Lina E. Jehane, Gwo-Shu Mary Lee, Lorelei A. Mucci, Nikolaus Schultz, Philip W. Kantoff. Identification and characterization of the PIK3R1-mutant subtype in PI3K-addicted prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2498.