TY - JOUR
T1 - RASAL2 confers collateral MEK/EGFR dependency in chemoresistant triple-negative breast cancer
AU - Koh, Siang Boon
AU - Ross, Kenneth
AU - Isakoff, Steven J.
AU - Melkonjan, Nsan
AU - He, Lei
AU - Matissek, Karina J.
AU - Schultz, Andrew
AU - Mayer, Erica L.
AU - Traina, Tiffany A.
AU - Carey, Lisa A.
AU - Rugo, Hope S.
AU - Liu, Minetta C.
AU - Stearns, Vered
AU - Langenbucher, Adam
AU - Saladi, Srinivas Vinod
AU - Ramaswamy, Sridhar
AU - Lawrence, Michael S.
AU - Ellisen, Leif W.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - 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 advancedTNBC(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 rewiresMAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors.
AB - 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 advancedTNBC(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 rewiresMAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors.
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UR - http://www.scopus.com/inward/citedby.url?scp=85114188181&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-0714
DO - 10.1158/1078-0432.CCR-21-0714
M3 - Article
C2 - 34168046
AN - SCOPUS:85114188181
SN - 1078-0432
VL - 27
SP - 4883
EP - 4897
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -