A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors
Menée in vitro et à l'aide de modèles murins de cancer colorectal avec mutation V600E au niveau du gène BRAF, cette étude met en évidence un mécanisme réversible par lequel un programme transcriptionnel inflammatoire impliquant la cyclo-oxygénase 2 et la kinase SRC favorise la résistance des cellules cancéreuses à l'inhibition de BRAF et EGFR
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.