Assessing the Activity of Alpelisib in Pathogenic Breast Cancer Mutations Utilizing Patient-Derived Xenografts

An urgent need for new treatment options for basal-like triple-negative breast cancers (TNBCs) exists. Mirroring the NCI-ComboMATCH study to identify new synergistic drug combinations that are cytotoxic for basal-like breast cancers, a set of 20 breast cancer patient-derived xenografts (PDXs) and 14 cell lines were analyzed to identify clinically actionable targets in each model.

The Oncomine Comprehensive Assay v3 was performed to assess 161 genes for hotspot mutations, focal copy number variants, amplifications/deletions, and RNA-fusion genes. Each PDX and their respective isogenic drug-resistant cell lines were analyzed with bulk RNA sequencing (218 samples) and single-cell RNA sequencing (~100,000 cells). Of all NCI match–defined targetable mutations, 37% of the models contained pathogenic PIK3CA amplifications or mutations. As PIK3CA was one of the most common oncogenic aberrations identified in patient tumors and the PI3K pathway was overactive in the majority of TNBCs, investigators sought to target PIK3CA across all models and to identify the drug partner with the most synergy.

Short-term cultures of tumor cells from each PDX were screened with a library of more than 1000 FDA-approved/experimental drugs to identify cytotoxic compounds. Synergistic drug assessments were performed with each drug in combination with the PI3K inhibitor alpelisib, a current standard of care for PI3K-mutant ER-positive disease. Synergism was identified using coefficient of drug interaction and 10 drugs were found to be synergistic across 3 PIK3CA aberration-containing models: UCD52, MDA453, and HCI-013. Afatinib, dronedarone, and everolimus were selected for CompuSyn-based synergism testing with 5 dose ratios, and each was confirmed to be synergistic with alpelisib in vitro. In vivo studies of each drug combination on 3 basal-like PDXs found all 3 combinations to be synergistic in UCD52, which is PIK3CA mutant and amplified.

The alpelisib and everolimus combination had significantly synergistic activity in 2 PTEN-deficient basal-like PDXs: WHIM30 and HCI-010. Initial studies found that UCD52 lung metastases were reduced using the alpelisib and everolimus combination. These combination therapies may provide clinical benefit for patients with chemotherapy-resistant metastatic disease, which warrants further exploration.

Source:

Boyd DC, Olex AL, Rashid NS, et al. Discovering synergistic compounds with alpelisib in PI3K overactivated TNBC patient-derived xenografts. San Antonio Breast Cancer Symposium 2022. Abstract P1-13-04.

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