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

Abstract

One Sentence Summary: Defective mismatch repair activates HER2 in HER2-negative breast cancer cells and renders them susceptible to HER2 inhibitors. Abstract: Estrogen receptor positive (ER + ) breast cancer is a leading cause of cancer-related death globally. Resistance to standard of care endocrine treatment occurs in at least 30% of ER + breast cancer patients resulting in ~40,000 deaths every year in the US alone. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance of ER + breast cancer that is HER2at diagnosis 1,2 . However, clinical trials of pan-HER inhibitors in ER + /HER2patients have disappointed, likely due to a lack of predictive biomarkers 3-6 . Here we demonstrate that loss of MLH1, a principal mismatch repair gene, causally activates HER2 in ER + /HER2breast cancer upon endocrine treatment. Additionally, we show that HER2 activation is indispensable for endocrine treatment resistant growth of MLH1cells in vitro and in vivo. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment in multiple experimental models including patient-derived xenograft tumors. Patient data from multiple clinical datasets (TCGA, METABRIC, Alliance (Z1031) and E-GEOD-28826) supports an association between MLH1 loss, HER2 upregulation, and sensitivity to trastuzumab in endocrine treatment-resistant ER + /HER2patients. These results provide strong rationale that MLH1 could serve as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine drugs and HER inhibitors in endocrine treatment-resistant ER + /HER2breast cancer patients. Implications of this study extend beyond breast cancer to Lynch Syndrome cancers. [Main Text: ]