Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer
Abstract
Resistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER+/HER2− patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER+/HER2− breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL- cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER+/HER2− patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER+/HER2− breast cancer patients.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 19, 2021
- Source ID
- 10.1038/s41467-021-23271-0
Entities
People
- Aloran Mazumder
- Ching Hui Chen
- Matthew J Ellis
- Nindo Punturi
- Rashi Kalra
- Shunqiang Li
- Shyam M. Kavuri
- Sinem Şeker
- Svasti Haricharan
- Tina Primeau
- Vaishnavi Devarakonda
Organizations
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute
- Susan G. Komen for the Cure
- United States Department of Defense
- United States Department of Health and Human Services