Abstract 5987: Mutations in <i>PIK3R1</i> activate multiple targetable pathways in triple-negative breast cancer

Abstract Background: Approximately 5% of triple-negative breast cancers (TNBCs) carry mutations in the PIK3R1 gene (PIK3R1MUT). Our prior studies showed that breast cancer cells lacking PIK3R1 protein had increased MEK activation, enhancing their responsiveness to the MEK inhibitors trametinib and binimetinib. Alpelisib targets the PI3K pathway. We hypothesized that alpelisib might also inhibit growth of PIK3R1MUT TNBC. This study tested binimetinib and alpelisib in PDX models with PIK3R1MUT. Methods: Five TNBC PDX models harboring either PIK3R1wt or PIK3R1MUT were studied (Table 1 ). Animals were treated with vehicle, binimetinib (10 mg/kg BID), alpelisib (35 mg/kg QD), or both for 28 days. Tumor volumes were recorded biweekly. All PDXs harbored PIK3CAwt but had mutations in other PI3K or MAPK genes. Mass spectrometry will be used to elucidate downstream protein and phosphoprotein expression. Results: Single-agent binimetinib or alpelisib did not result in significant tumor growth reduction in Models A and B. Binimetinib alone resulted in a slightly significant effect in Model C. However, a highly significant effect of both single agents was observed in Model D (p=0.0001). Binimetinib and alpelisib in combination significantly reduced tumor growth in all models, particularly in model D (p=0.0126, p=0.009, p=0.0011, and p&amp;lt;0.0001 in Models A-D, respectively). The mass spectrometry results, and efficacy data from Model E will be presented at the meeting. Conclusions: Mutations in PIK3R1 sensitize TNBCs to combined MEK and PI3K pathway inhibition. NF1 mutations alone do not confer sensitivity to single agents but enhance response when combined with binimetinib and alpelisib. These findings support the combination of MEK and PIK3CA inhibitors as a potential strategy for treating PIK3CAMUT TNBCs. Disclaimer: AMA is employed by AstraZeneca but contributed to this publication in his own capacity. The views expressed are his own and do not necessarily represent the views of AstraZeneca. Citation Format: Abde M. Abukhdeir, Kelly Cagin, Jeffrey Borgia, Melody Cobleigh. Mutations in PIK3R1 activate multiple targetable pathways in triple-negative breast 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 5987.