A reversible SRC-relayed COX2-inflammatory program drives therapeutic resistance in BRAF(V600E) colorectal tumors

Ruiz-Saenz, A.; Atreya, C. E.; Wang, C.; Pan, B.; Dreyer, C. A.; Brunen, D.; Prahallad, A.; Munoz, D. P.; Ramms, D. J.; Burghi, V.; Spassov, D. S.; Fewings, E.; Hwang, Y. C.; Cowdrey, C.; Moelders, C.; Schwarzer, C.; Wolf, D. M.; Hann, B.; VandenBerg, S. R.; Shokat, K.; Moasser, M. M.; Bernards, R.; Gutkind, J. S.; van't Veer, L. J.; Coppe, J.-P.

doi:10.1101/2022.10.20.512885

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bioRxiv · 10.1101/2022.10.20.512885

A reversible SRC-relayed COX2-inflammatory program drives therapeutic resistance in BRAF(V600E) colorectal tumors

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Abstract

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. We found 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 efficacy in vitro and in 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 BRAFV600E CRC.

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Ruiz-Saenz, A., Atreya, C. E., Wang, C., Pan, B., Dreyer, C. A., Brunen, D., Prahallad, A., Munoz, D. P., Ramms, D. J., Burghi, V., Spassov, D. S., Fewings, E., Hwang, Y. C., Cowdrey, C., Moelders, C., Schwarzer, C., Wolf, D. M., Hann, B., VandenBerg, S. R., Shokat, K., Moasser, M. M., Bernards, R., Gutkind, J. S., van't Veer, L. J., Coppe, J.-P.. 2022-10-21. A reversible SRC-relayed COX2-inflammatory program drives therapeutic resistance in BRAF(V600E) colorectal tumors. https://doi.org/10.1101/2022.10.20.512885

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