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Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer

Nindo B Punturi1, Sinem Seker1, Vaishnavi Devarakonda2,3

  • 1Tumor Microenvironment and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Nature Communications
|May 20, 2021
PubMed

Insights

Loss of mismatch repair (MutL loss) in ER-positive breast cancer activates HER2, driving endocrine treatment resistance. Inhibiting HER2 restores sensitivity, identifying MutL loss as a predictive biomarker for combination therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Endocrine therapy resistance affects ~30% of ER-positive breast cancer patients, contributing to significant mortality.
  • Growth factor receptor HER2 activation is implicated in endocrine resistance, but clinical trials with pan-HER inhibitors have yielded disappointing results in ER+/HER2- patients.
  • Lack of predictive biomarkers hinders effective treatment strategies for endocrine-resistant breast cancer.

Purpose of the Study:

  • To investigate the role of mismatch repair deficiency in endocrine therapy resistance in ER-positive breast cancer.
  • To identify biomarkers predicting response to HER2-targeted therapies in combination with endocrine treatment.
  • To elucidate the mechanism of HER2 activation in endocrine-resistant breast cancer cells with loss of mismatch repair.

Main Methods:

  • Utilized ER-positive breast cancer cell lines with and without mismatch repair deficiency (MutL-).
  • Investigated HER2 protein trafficking and activation following endocrine treatment.
  • Assessed the efficacy of HER2 inhibition in restoring endocrine sensitivity in MutL- cells.
  • Analyzed clinical patient datasets for correlations between MutL status, HER2 expression, and response to HER inhibitors.

Main Results:

  • Loss of mismatch repair (MutL loss) leads to HER2 activation in ER+/HER2- breast cancer cells by disrupting HER2 protein trafficking.
  • HER2 activation is essential for endocrine treatment resistance in MutL- breast cancer cells.
  • Inhibition of HER2 resensitizes MutL- cells to endocrine treatment.
  • Clinical data confirms an association between MutL loss, elevated HER2 levels, and sensitivity to HER inhibitors in ER+/HER2- patients.

Conclusions:

  • MutL loss is a novel mechanism driving endocrine therapy resistance in ER-positive breast cancer via HER2 activation.
  • MutL loss serves as a predictive biomarker for sensitivity to combination therapy with endocrine agents and HER2 inhibitors.
  • This finding provides a strong rationale for targeting HER2 in endocrine-resistant ER+/HER2- breast cancer patients with MutL deficiency.

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