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

• Published in: Nature communications 2021-05, Vol.12 (1), p.2940-11, Article 2940
• Main Authors: Punturi, Nindo B., Seker, Sinem, Devarakonda, Vaishnavi, Mazumder, Aloran, Kalra, Rashi, Chen, Ching Hui, Li, Shunqiang, Primeau, Tina, Ellis, Matthew J., Kavuri, Shyam M., Haricharan, Svasti
• Format: Article
• Language: English
• Subjects: 45/22; 45/44; 631/337/1427; 631/67/1059; 82/1; 82/51; 82/79; 82/80; 96/106; 96/109; 96/31; 96/95; Animals; Biomarkers; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Line, Tumor; Clinical trials; Combinatorial analysis; DNA Mismatch Repair - drug effects; DNA Mismatch Repair - genetics; Drug Resistance, Neoplasm - genetics; ErbB-2 protein; Female; Gene Knockdown Techniques; Growth factors; Humanities and Social Sciences; Humans; Inhibitors; MCF-7 Cells; Mice; Mice, Nude; Mice, SCID; Mismatch repair; multidisciplinary; MutL Protein Homolog 1 - genetics; MutL Protein Homolog 1 - metabolism; MutL Proteins - genetics; MutL Proteins - metabolism; Patients; Protein transport; Proteins - metabolism; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - metabolism; Repair; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Sensitivity; Signal Transduction; Treatment resistance; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23271-0

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.