Discovering Synergistic Compounds with BYL-719 in PI3K Overactivated Basal-like PDXs

SIMPLE SUMMARY: Basal-like breast cancers comprise the majority of triple-negative breast cancers (TNBC) and lack effective treatment options that have a sustained response. Part of the reason that they are hard to eliminate is that they exhibit high levels of genomic instability and cellular diversity. Most basal-like tumors have high levels of Phosphoinositide 3-Kinase (PI3K) pathway activity. A key driver of this pathway is PIK3CA. Many compounds have been made to target PIK3CA and have become standard-of-care in some estrogen-dependent patients; however, in TNBC patients, PI3K inhibitors (PI3Ki) as single agents thus far have shown limited duration at tolerable doses. The goal of this study was to identify and/or repurpose drugs that, when combined with PI3Ki, yield a significant inhibition of tumor growth. When treated in conjunction with the PI3Ki BYL-719, which is clinically prescribed as alpelisib, 20 potent drug combinations were identified and formed a basis toward clinical studies with these molecules. ABSTRACT: Basal-like triple-negative breast cancer (TNBC) tumor cells are difficult to eliminate due to resistance mechanisms that promote survival. While this breast cancer subtype has low PIK3CA mutation rates when compared to estrogen receptor-positive (ER+) breast cancers, most basal-like TNBCs have an overactive PI3K pathway due to gene amplification or high gene expression. BYL-719 is a PIK3CA inhibitor that has been found to have low drug-drug interactions, which increases the likelihood that it could be useful for combinatorial therapy. Alpelisib (BYL-719) with fulvestrant was recently approved for treating ER+ breast cancer patients whose cancer had developed resistance to ER-targeting therapy. In these studies, a set of basal-like patient-derived xenograft (PDX) models was transcriptionally defined with bulk and single-cell RNA-sequencing and clinically actionable mutation profiles defined with Oncomine mutational profiling. This information was overlaid onto therapeutic drug screening results. BYL-719-based, synergistic two-drug combinations were identified with 20 different compounds, including everolimus, afatinib, and dronedarone, which were also found to be effective at minimizing tumor growth. These data support the use of these drug combinations towards cancers with activating PIK3CA mutations/gene amplifications or PTEN deficient/PI3K overactive pathways.