Integrative Proteogenomics and Forward Genetics Reveal a Novel Mitotic Vulnerability in Triple-Negative Breast Cancer

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTA) are first-line chemotherapies for TNBC; however, the molecular mechanisms that underlie TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening. We discovered that PTPN12 inactivation drives mitotic defects through aberrant hyperactivation of the ubiquitin ligase complex APCFZR1, a critical regulator of the cell cycle. Consistent with the mitotic stress caused by PTPN12 inactivation in TNBC cell lines, tumors harboring loss of PTPN12 exhibit heightened sensitivity to taxane chemotherapy. Collectively, these data suggests that PTPN12 inactivation may drive chromosomal instability and favorable MTA response in TNBC—two prominent features of the disease with unclear mechanistic etiology. Significance: Many TNBCs respond to MTAs, but the underlying cause(s) of this sensitivity remain poorly understood. Herein, we discover that the tumor suppressor PTPN12 regulates mitotic fidelity and MTA sensitivity in a large subset of patients with TNBC, which has significant implications for the use of MTAs in breast cancer.