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A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors

2023; Nature Portfolio; Linguagem: Inglês

10.1038/s43018-022-00508-5

2662-1347

Ana Ruiz-Sáenz, Chloé E. Atreya, Changjun Wang, Bo Pan, Courtney A. Dreyer, Diede Brunen, Anirudh Prahallad, Denise P. Muñoz, Dana J. Ramms, Valeria Burghi, Danislav S. Spassov, Eleanor Fewings, Yeonjoo Hwang, Cynthia Cowdrey, Christina Moelders, Cecilia Schwarzer, Denise M. Wolf, Byron Hann, Scott R. VandenBerg, Kevan M. Shokat, Mark M. Moasser, René Bernards, J. Silvio Gutkind, Laura van ′t Veer, Jean‐Philippe Coppé,

Cytokine Signaling Pathways and Interactions

Abstract BRAF V600E 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 BRAF V600E 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 E 2 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 BRAF V600E CRC.