Author:
Ruiz-Saenz Ana,Atreya Chloe E.,Wang Changjun,Pan Bo,Dreyer Courtney A.,Brunen Diede,Prahallad Anirudh,Muñoz Denise P.,Ramms Dana J.,Burghi Valeria,Spassov Danislav S.,Fewings Eleanor,Hwang Yeonjoo C.,Cowdrey Cynthia,Moelders Christina,Schwarzer Cecilia,Wolf Denise M.,Hann Byron,VandenBerg Scott R.,Shokat Kevan,Moasser Mark M.,Bernards René,Gutkind J. Silvio,van ‘t Veer Laura J.,Coppé Jean-Philippe
Abstract
ABSTRACTBRAFV600Emutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF/MEK/EGFR co-targeting, we used a high throughput kinase activity mapping platform. We found that SRC kinases are systematically activated in BRAFV600ECRC following targeted inhibition of BRAF ± EGFR, and that coordinated targeting of SRC with BRAF ± EGFR increases efficacyin vitroandin vivo. SRC drives resistance to BRAF ± anti-EGFR therapy independently of ERK signaling by inducing transcriptional reprogramming via beta-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E2-loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF+EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft (PDX) models. COX2 inhibition represents a novel drug-repurposing strategy to overcome therapeutic resistance in BRAFV600ECRC.
Publisher
Cold Spring Harbor Laboratory