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Discovering Synergistic Compounds with BYL-719 in PI3K Overactivated Basal-like PDXs
David C Boyd1,2, Emily K Zboril1, Amy L Olex3
1Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA.
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.
Insights
This study identifies effective drug combinations for basal-like triple-negative breast cancer (TNBC) by targeting the PI3K pathway. BYL-719 (alpelisib) combined with other drugs shows promise in minimizing tumor growth in TNBC models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Basal-like triple-negative breast cancer (TNBC) exhibits resistance to treatment due to survival mechanisms.
- While PIK3CA mutations are less common in TNBC than ER+ breast cancer, the PI3K pathway is often overactive due to gene amplification or high expression.
- BYL-719 (alpelisib) is a PIK3CA inhibitor with low drug-drug interaction potential, suggesting its utility in combination therapies.
Purpose of the Study:
- To identify synergistic drug combinations involving BYL-719 for treating basal-like TNBC.
- To investigate the efficacy of these combinations in patient-derived xenograft (PDX) models with defined molecular profiles.
- To support the clinical application of BYL-719-based combinations in TNBC with PI3K pathway alterations.
Main Methods:
- Characterization of basal-like TNBC PDX models using bulk and single-cell RNA-sequencing for transcriptional profiling.
- Oncomine mutational profiling to define clinically actionable mutations.
- Therapeutic drug screening to identify synergistic BYL-719-based two-drug combinations.
Main Results:
- Over 20 synergistic two-drug combinations with BYL-719 were identified.
- Compounds such as everolimus, afatinib, and dronedarone demonstrated efficacy in minimizing tumor growth when combined with BYL-719.
- These combinations were effective in models with PIK3CA activating mutations/amplifications or PTEN deficiency/PI3K overactivity.
Conclusions:
- BYL-719-based combination therapies show significant potential for treating basal-like TNBC.
- These findings support the use of specific drug combinations in patients with PI3K pathway-altered TNBC.
- Further clinical investigation of these synergistic combinations is warranted.
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