Work

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

Year: 2021

Type: article

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 HER2 - at diagnosis 1,2 . However, clinical trials of pan-HER inhibitors in ER + /HER2 - patients 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 + /HER2 - breast cancer upon endocrine treatment. Additionally, we show that HER2 activation is indispensable for endocrine treatment resistant growth of MLH1 - cells 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 + /HER2 - patients. 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 + /HER2 - breast cancer patients. Implications of this study extend beyond breast cancer to Lynch Syndrome cancers. One Sentence Summary Defective mismatch repair activates HER2 in HER2-negative breast cancer cells and renders them susceptible to HER2 inhibitors.

Source: Nature Communications

DOI: 10.1038/s41467-021-23271-0