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