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A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors.
- 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
Published Web Location
https://doi.org/10.1038/s43018-022-00508-5Abstract
BRAFV600E mutation 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. Here we show that SRC kinases are systematically activated in BRAFV600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through β-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 models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAFV600E CRC.
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