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Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer
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Journal Article
Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer
2021
Overview
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.
Resistance to endocrine treatment in ER+/HER2- breast cancer patients remains a significant clinical problem. Here, the authors demonstrate that loss of the MutL mismatch repair complex can serve as a first-in-class predictive biomarker for combinatorial inhibition of HER2 to overcome the emergence of endocrine treatment resistance.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 45/44
/ 82/1
/ 82/51
/ 82/79
/ 82/80
/ 96/106
/ 96/109
/ 96/31
/ 96/95
/ Animals
/ Breast Neoplasms - drug therapy
/ Breast Neoplasms - metabolism
/ DNA Mismatch Repair - drug effects
/ DNA Mismatch Repair - genetics
/ Drug Resistance, Neoplasm - genetics
/ Female
/ Humanities and Social Sciences
/ Humans
/ Mice
/ MutL Protein Homolog 1 - genetics
/ MutL Protein Homolog 1 - metabolism
/ Patients
/ Receptor, ErbB-2 - antagonists & inhibitors
/ Receptor, ErbB-2 - metabolism
/ Receptors, Estrogen - metabolism
/ Repair
/ Science
