Abstract P6-11-01: A broad spectrum therapeutic strategy for TNBC revealed by a new pathway that coordinates oncogenic RTKs

Abstract

Abstract Triple-negative breast cancer (TNBC) is a collection of diseases with distinct clinical behaviors and heterogeneous molecular features. Such clinical and genetic heterogeneity has called into question whether there are common pathogenic mechanisms (and potential therapeutic targets) driving the TNBC subtype of breast cancer. Herein, we present evidence of a novel tumor suppressor network that is frequently compromised in TNBC, and a broadly-effective strategy to target this pathway for TNBC therapeutic intervention. Using an unbiased genetic screen, we identified a tumor suppressor network governing tumor survival of TNBCs in vitro and in vivo. We define the tyrosine phosphatase PTPN12 as a core component in this network. PTPN12 is a potent suppressor of mammary epithelial cell survival and transformation, and PTPN12 function is compromised in more than 70% of human TNBCs. Notably, the tumorigenic and metastatic potential of PTPN12-deficient TNBCs is severely impaired by restoring PTPN12, suggesting that strategies to mimic PTPN12 function have substantive therapeutic potential. Using integrative proteomic, genetic, and pharmacologic approaches, we demonstrate that PTPN12 suppresses TNBC survival by inhibiting multiple oncogenic receptor tyrosine kinases (TKs) including MET, PDGFRβ, and others. Frequent inactivation of PTPN12 in human TNBC unleashes these oncogenic TKs in a concerted manner. Importantly, combination inhibitors targeting these PTPN12-regulated TKs significantly impair TNBC cell survival and confer robust tumor regression across a panel of 18 patient-derived xenograft ("PDX") models of human TNBC. This suggests that TNBCs are broadly dependent on a distinct combination of proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor in TNBC and provide a rationale for combinatorially targeting select receptor tyrosine kinases in TNBC and other cancers based on their defects in tyrosine phosphatase activity. Citation Format: Thomas F Westbrook, Amritha Nair, Tingting Sun, Kristen L Karlin, Jessica Kessler, Ilenia Migliaccio, Don X Nguyen, Ronald J Bernardi, Alex Renwick, Chad J Creighton, Noah Dephoure, Steven P Gygi, Chad A Shaw, Richard Gibbs, David Wheeler, Rachel Schiff, James G Christensen, David J Shields, C Kent Osborne, Stephen J Elledge, Susan G Hilsenbeck, Michael T Lewis. A broad spectrum therapeutic strategy for TNBC revealed by a new pathway that coordinates oncogenic RTKs [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-01.