RASAL2 Confers Collateral MEK/EGFR Dependency in Chemoresistant Triple-Negative Breast Cancer
Year: 2021
Type: article
Abstract: Purpose: While chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens. Experimental Design: We performed transcriptional profiling of tumors from a phase II clinical trial of platinum chemotherapy for advanced TNBC (TBCRC-009), revealing a gene expression signature that identified de novo chemorefractory tumors. We then employed pharmacogenomic data mining, proteomic and other molecular studies to define the therapeutic vulnerabilities of these tumors. Results: We reveal the RAS-GTPase-activating protein (RAS-GAP) RASAL2 as an upregulated factor that mediates chemotherapy resistance but also an exquisite collateral sensitivity to combination MAP kinase kinase (MEK1/2) and EGFR inhibitors in TNBC. Mechanistically, RASAL2 GAP activity is required to confer kinase inhibitor sensitivity, as RASAL2-high TNBCs sustain basal RAS activity through suppression of negative feedback regulators SPRY1/2, together with EGFR upregulation. Consequently, RASAL2 expression results in failed feedback compensation upon co-inhibition of MEK1/2 and EGFR that induces synergistic apoptosis in vitro and in vivo. In patients with TNBC, high RASAL2 levels predict clinical chemotherapy response and long-term outcomes, and are associated via direct transcriptional regulation with activated oncogenic Yes-Associated Protein (YAP). Accordingly, chemorefractory patient-derived TNBC models exhibit YAP activation, high RASAL2 expression, and tumor regression in response to MEK/EGFR inhibitor combinations despite well-tolerated intermittent dosing. Conclusions: These findings identify RASAL2 as a mediator of TNBC chemoresistance that rewires MAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors.
Source: Clinical Cancer Research
Authors: Siang-Boon Koh, Kenneth Ross, Steven J. Isakoff, Nsan Melkonjan, Lei He, Karina J. Matissek, Andrew Schultz, Erica L. Mayer, Tiffany A. Traina, Lisa A. Carey, Hope S. Rugo, Minetta C. Liu, Vered Stearns, Adam Langenbucher, Srinivas Vinod Saladi, Sridhar Ramaswamy, Michael S. Lawrence, Leif W. Ellisen
Institutions: Harvard University, Massachusetts General Hospital, Broad Institute, Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, University of North Carolina at Chapel Hill, University of California, San Francisco, Georgetown Lombardi Comprehensive Cancer Center, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W3174841475