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Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways

Qing-Bai She1,2,3, Sofia K Gruvberger-Saal4,5, Matthew Maurer6,7

  • 1Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

BMC Cancer
|August 4, 2016
PubMed
Abstract

Insights

Targeting the PI3K pathway alongside EGFR shows promise for basal-like breast cancer (BLBC). This combination therapy demonstrated synergistic effects in preclinical models, offering a new therapeutic strategy for this aggressive cancer subtype.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Basal-like breast cancer (BLBC) lacks targeted therapies and has a poor prognosis.
  • Oncogenic signaling pathways driving BLBC are not fully understood.

Purpose of the Study:

  • Investigate PI3K pathway aberrations in BLBC.
  • Evaluate therapeutic combinations targeting PI3K and EGFR pathways in BLBC.

Main Methods:

  • Integrated analysis of PI3K pathway molecular aberrations in 116 breast tumors.
  • Validation in an independent series.
  • In vitro and in vivo studies of combination therapies.

Main Results:

  • 75% of tumors had aberrations in PI3K pathway or related kinases (HER2, EGFR).
  • PTEN-loss correlated with BLBC markers and subtype.
  • Combination of EGFR inhibitor (gefitinib) and PI3K inhibitor (LY294002/PWT-458) showed synergistic tumor cell killing and regression in vivo.

Conclusions:

  • PI3K/PTEN pathway is crucial in ER-negative and basal-like breast cancer.
  • Combination therapy targeting EGFR and PI3K pathways warrants clinical evaluation for BLBC treatment.
Keywords:
Basal-likeBreast cancerCombination therapyEGFRPTEN

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