biostudies-literatureNeill NJWelch Foundation (The Welch Foundation)Cancer Research UKNCRR NIH HHSNational Institutes of Health (NIH)NIAID NIH HHSNCI NIH HHSMark Foundation For Cancer Research (The Mark Foundation for Cancer Research)2326-2343https://www.ebi.ac.uk/biostudies/studies/S-EPMC12641601biostudies-literatureUnknown15(11)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. ConsistCancer discoveryIntegrative Proteogenomics and Forward Genetics Reveal a Novel Mitotic Vulnerability in Triple-Negative Breast Cancer.PMC12641601U01-CA214125U24-CA210986U24 CA270823R01 CA178039P50 CA186784P30 CA125123U24 CA210979U24-CA270823U24 CA210954P30 AI036211P50 CA058223U24 CA210986U54 CA224076S10 RR024574U01 CA214125R01-CA178039Huang CMeerbrey KLWheeler DAPerou CMMiles GCalderon COrellana MZhang PZhang BSun JLi HLewis MTSun TGutierrez CKim BJYang DLin CYCarr SASatpathy SLewis AAvanessian SCPolley MCKrug KCardenas MFRamesh Babu NChan DWMao SAnurag MSaltzman ABWestbrook TFBowling EAGong FGillette MAHolloway KRWang JHMani DRDobrolecki LEOlson CMVasaikar SOsborne CKMeena JKWeber MJChung HCStossi FHilsenbeck SGSallas CNeill NJXiao PKurley SJGray NSMalovannaya AEllis MJMundt FReed DTyagi SNair AfalseIntegrative Proteogenomics and Forward Genetics Reveal a Novel Mitotic Vulnerability in Triple-Negative Breast Cancer.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. Consist2025-01-01T00:00:00Z2025 Nov2026-06-05T18:36:44.809Z2026-05-20T03:13:38.299ZS-EPMC126416014077881810.1158/2159-8290.CD-23-117310.1158/2159-8290.cd-23-1173