Abstract 6650: Targeting the PI3K pathway with alpelisib in patient-derived xenografts: a multi-cancer type approach

Abstract Phosphoinositide 3-kinase (PI3K) pathway has a crucial role in the regulation of cellular proliferation, survival, and metabolism. Frequent aberrant activation of this pathway is one of the most common oncogenic events across various human cancer types including breast (ER+), colorectal, lung, kidney, and skin cancers. We collected and analyzed baseline tandem mass tag (TMT) proteomics data (protein and phosphorylation levels) for 40 samples from 36 PIK3CA PDX models across five cancer types (RCC, Melanoma, CRC, BRCA, and LUAD). Initial Pearson correlation analysis revealed that most samples clustered by cancer type, indicating that tissue specificity contributes more to molecular similarities than oncogenic mutations. When focusing on components of the PI3K pathway, we observed diverse protein levels and activation statuses across the cohort of PDX models. In breast cancer (BRCA), colorectal (CRC), and kidney (RCC) samples, we noted elevated levels of total and phosphorylated AKT, which were lower in lung squamous cell carcinoma (LUSC) and melanoma samples. Interestingly, we also found heterogeneous activation statuses of components in the PI3K pathway in BRCA samples. A subset of BRCA samples exhibited high levels of total AKT and phosphorylation at T479 and S477, alongside elevated TSC1 and TSC2 activation. Since TSC proteins are known to inhibit PI3K pathway activity, their elevation could indicate feedback inhibition of the pathway even with PIK3CA mutations. To further elucidate the diverse treatment response profile of the PIK3CA mutant PDX lines across cancer types in mice, we assembled a cohort of 3 cancer types, BRCA, ccRCC, and PDAC. Despite the varied mutation profiles, we observed that responses to Alpelisib differed among the RCC PDX lines, with insignificant effects in PDMR-274T, no response in RESL4, and a modest effect in RESL10. In the BRCA study, out of 6 treated ER+ PDX lines, we observed significant responses in WHIM9 and WHIM20. Moderate responses were seen in WHIM84 and WHIM18, while HCI-011 and WHIM16 showed no response. Proteogenomic analyses are ongoing to discern response biomarkers. Citation Format: Kapur B. Dhami, Chiya-Kuei Mo, Zhanfang Guo, Richard Kurupi, Preet Lal, Kazuhito Soto, Xiyi Wei, Michael C. Wendl, Jacqueline Mudd, Shunqiang Li, Sherri R. Davies, Jeff Chuang, Bingliang Fang, Ryan Fields, Hui Zhang, Meenhard Herlyn, Feng Chen, Kian-Huat Lim, Kian-Huat Lim, Cynthia Ma, Li DIng. Targeting the PI3K pathway with alpelisib in patient-derived xenografts: a multi-cancer type approach [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 6650.