Abstract 5401: Revealing the influence of reprogrammed PI3K and glucose metabolism on the progression of hormone-refractory and metastatic prostate cancer
Authors: Prathiksha Prabhakaraalva, Nabila Zaman, Sarah Ann King, Goutam Chakraborty
Journal: Cancer Research (2025)

Abstract Background: Prostate cancer, despite advancements in early detection and therapies, remains an incurable disease when it transform to metastatic and castration-resistant. A significant knowledge gap exists in understanding the mechanistic insights that drives hormone-refractory progression and metastasis. The PI3-Kinase pathway, altered in over &amp;gt;50 % of metastatic prostate cancer cases, plays a pivotal role in oncogenesis and therapy resistant. Although PTEN deletions are well-characterized, the specific contributions of other PI3K pathway components, particularly PIK3R1 mutations, remain underexplored. Our previous study reported that PIK3R1 mutations are highly enriched in metastatic castration-resistant prostate cancer (mCRPC) and are associated with increased glucose uptake detected by FDG-PET scans. Therefore, these mutations are crucial for further investigation. Method: We generated 22 patients derived naturally occurring prostate cancer specific PIK3R1 mutations by site directed mutagenesis and verified their expression by western blotting. Using CRISPR and shRNA we have also established double PIK3R1-PTEN null prostate cancer cells. Prostasphere experiments was performed to analyzed the impact of these double loss on prostate cell growth in vitro Isogenic pairs of these double-knockout prostate cancer cells were treated with increasing concentrations of insulin in the under serum starvation to study the impact of PIK3R1-PTEN loss on reprogramming of insulin-glucose metabolism and oncogenic signaling pathways associated with this reprogramming Results: Our results reveal that PIK3R1 mutations exhibit distinct, mutation-specific effects on PI3K-AKT signaling, where some variants induce AKT phosphorylation and destabilize PTEN, while others inhibit AKT and stabilize PTEN, underscoring diverse roles of specific PIK3r1 mutation within the PI3K pathway. Interestingly, PIK3R1-KO cells displayed heightened androgen receptor (AR) pathway activity and enhanced tumor sphere formation, suggesting increased tumorigenic potential. Furthermore elevated levels phosphorylated mTOR in PIK3R1 knockout clones indicate potential mechanisms of oncogenesis, which may further drive metastatic progression. Our primary data also demonstrated that insulin treatment in PIK3R1-PTEN null cells alters androgen receptor (AR) function, indicating a direct association between PIK3R1-PTEN-glucose metabolisms and AR-signaling that is crucial for prostate tumor growth. Conclusion: Our findings emphasize the critical role of PIK3R1 in both AR and PI3K-AKT-mTOR signaling cascades, offering insights into the complex interplay of PIK3R1 mutations in therapy-resistant prostate cancer. This research underscores the need to explore mutation-specific PIK3R1 effects as we move toward more personalized therapies for lethal mCRPC. Citation Format: Prathiksha Prabhakaraalva, Nabila Zaman, Sarah Ann King, Goutam Chakraborty. Revealing the influence of reprogrammed PI3K and glucose metabolism on the progression of hormone-refractory and metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5401.