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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.

Cancers
|March 11, 2023
PubMed
Summary

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.

Keywords:
BYL-719 (alpelisib)afatinibbasal-like breast cancerdronedaroneeverolimuspatient-derived xenograftprecision medicinesynergismtriple-negative breast cancer

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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.