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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

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Mechanism of trastuzumab resistance caused by HER-2 mutation in breast carcinomas

Xiangyi Kong1,2, Kai Zhang3, Xiangyu Wang1,4

  • 1Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.

Cancer Management and Research
|July 17, 2019
PubMed

Insights

HER2 mutations in breast cancer can cause resistance to trastuzumab treatment by affecting the PI3K/AKT pathway. Inhibiting this pathway can restore sensitivity to trastuzumab in HER2-mutant cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Trastuzumab is a key therapy for HER2-positive breast cancer.
  • Drug resistance, both primary and secondary, limits trastuzumab's efficacy.
  • Understanding resistance mechanisms is crucial for improving treatment outcomes.

Purpose of the Study:

  • To investigate the role of HER2 mutations in trastuzumab resistance in breast cancer.
  • To elucidate the molecular mechanisms underlying this resistance.
  • To identify potential therapeutic strategies to overcome resistance.

Main Methods:

  • Established HER2 wild-type (WT) and mutant (Q429R, Q429H, T798M) MCF7 cell lines.
  • Assessed cell proliferation using Cell Counting Kit-8 and BrdU assays.
  • Evaluated metastatic potential via Transwell invasion assays.
  • Analyzed protein expression and HER2-trastuzumab interaction using Western blotting and co-immunoprecipitation.
  • Investigated the impact on PI3K/AKT signaling pathways.

Main Results:

  • HER2 mutant cells exhibited reduced sensitivity to trastuzumab compared to WT cells.
  • HER2 mutations did not significantly alter HER2 expression or trastuzumab binding.
  • HER2 mutations attenuated trastuzumab's inhibitory effect on PI3K/AKT pathways.
  • Inhibiting the PI3K/AKT pathway enhanced trastuzumab sensitivity in HER2-mutant cells.

Conclusions:

  • PI3K-AKT pathway dysregulation is a critical mechanism driving trastuzumab resistance in HER2-mutant breast cancer.
  • Targeting the PI3K-AKT pathway may represent a viable strategy to re-sensitize HER2-mutant breast cancer to trastuzumab.
Keywords:
HER2PI3Kresistancetrastuzumab

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