The impact of PIK3R1 mutations and insulin-PI3K-glycolytic pathway regulation in prostate cancer.

Oncogenic alterations of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway occur in >40% of patients with metastatic castration-resistant prostate cancer (mCRPC), predominantly via PTEN loss. The significance of other PI3K pathway components in prostate cancer is largely unknown.

Patients in this study underwent tumor sequencing using the MSK-IMPACT clinical assay to capture single-nucleotide variants, insertions, and deletions, copy number alterations, and structural rearrangements, or were profiled through The Cancer Genome Atlas. The association between PIK3R1 alteration/expression and survival was evaluated using univariable and multivariable Cox proportional-hazards regression models. We used siRNA-based knockdown of PIK3R1 for functional studies. FDG-PET/CT examinations were performed with a hybrid PET/CT scanner for some prostate cancer patients in MSK-IMPACT cohort.

Analyzing 1417 human prostate cancers, we found a significant enrichment of PIK3R1 alterations in metastatic cancers compared to primary cancers. PIK3R1 alterations or reduced mRNA expression tended to be associated with worse clinical outcomes in prostate cancer, particularly in primary disease, as well as in breast, gastric, and several other cancers. In prostate cancer cell lines, PIK3R1 knockdown resulted in increased cell proliferation and AKT activity, including insulin-stimulated AKT activity. In cell lines and organoids, PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors. PIK3R1-altered patient prostate tumors had increased uptake of the glucose analogue 18F-fluorodeoxyglucose in PET imaging, suggesting increased glycolysis.

Our findings describe a novel genomic feature in metastatic prostate cancer and suggest that PIK3R1 alteration may be a key event for insulin-PI3K-glycolytic pathway regulation in prostate cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Jun 07 [Epub ahead of print]

Goutam Chakraborty, Subhiksha Nandakumar, Rahim Hirani, Bastien Nguyen, Konrad H Stopsack, Christoph Kreitzer, Sai Harisha Rajanala, Romina Ghale, Ying Z Mazzu, Naga Vara Kishore Pillarsetty, Gwo-Shu Mary Lee, Howard I Scher, Michael J Morris, Tiffany Traina, Pedram Razavi, Wassim Abida, Jeremy C Durack, Stephen B Solomon, Matthew G Vander Heiden, Lorelei A Mucci, Andreas G Wibmer, Nikolaus Schultz, Philip W Kantoff

Icahn School of Medicine at Mount Sinai, New York, United States., Memorial Sloan Kettering Cancer Center, New York, NY, United States., Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium., Harvard T.H. Chan School of Public Health, Boston, MA, United States., Memorial Sloan Kettering Cancer Center, New York, United States., Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States., Memorial Sloan Kettering Cancer Center; Weill Cornell College of Medicine, New York, NY, United States., Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, United States., Massachusetts Institute of Technology, Cambridge, United States.

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