Abstract PS4-02-19: Mutations in PIK3R1 Activate Multiple Pathways in Triple Negative Breast Cancer

Abstract Background: Approximately 6% of triple-negative breast cancers (TNBCs) carry mutations in the PIK3R1 gene (PIK3R1MUT). We previously showed that PIK3R1 knock-out causes increased phosphorylation of MEK and enhanced sensitivity to MEK inhibitors, trametinib and binimetinib. Alpelisib targets p110-α in the PI3K/AKT/mTOR pathway. We hypothesized that alpelisib might also inhibit growth of PIK3R1 MUT TNBC. This study tested binimetinib, alpelisib, and their combination in PDX models with PIK3R1 MUT . Methods: Four TNBC PDX models were studied (Table 1). All models had wild-type PIK3CA. Control mice had wild-type PIK3R1, while experimental mice had PIK3R1 MUT . Animals were treated with vehicle control, binimetinib (10 mg/kg BID), alpelisib (35 mg/kg QD), or their combination for at least 28 days. Tumor volumes were recorded biweekly. The genetic backgrounds of each model are listed. All mice had co-mutations in PI3K or MAPK pathway genes but lacked co-mutations in both pathways. Tumors were analyzed using mass spectrometry to elucidate downstream protein and phosphoprotein expression. Results: Endpoint analyses showed no significant tumor growth reduction with single-agent binimetinib or alpelisib in Models A and B. Binimetinib alone resulted in a slightly significant effect in Model C (p<0.01). However, a highly significant effect of both single agents was observed in Model D (p<0.001). Combination therapy with binimetinib and alpelisib significantly reduced tumor growth in all models but was most effective in models C and D (p<0.001, p<0.001, p<0.0001, and p<0.0001 in Models A-D, respectively). The mass spectrometry results will be presented at the meeting. Conclusions: Mutations in PIK3R1 sensitize TNBCs to combined MEK and PI3K pathway inhibition. Co-mutations in PIK3R1 wt PDX models may also sensitize TNBC to MEK and PI3K inhibitors. These findings suggest that combining inhibitors of MEK and PIK3CA could inhibit growth of TNBCs. Disclaimer: AA 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: A. Abukhdeir, K. Cagin, J. Borgia, M. Cobleigh. Mutations in PIK3R1 Activate Multiple Pathways in Triple Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-02-19.