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Cited by 39Colorectal Cancer Treatments and StudiesMelanoma and MAPK PathwaysLung Cancer Treatments and Mutations

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

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Ruiz-Saenz, Ana, Atreya, Chloe E., Wang, Changjun, Pan, Bo, Dreyer, Courtney A., Brunen, Diede, Prahallad, Anirudh, Muñoz, Denise P. +17 more·2023·Nature Cancer
DOI 10.1038/s43018-022-00508-5PMC PMC9970872
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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. 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.

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  • Ruiz-Saenz et al. revealed that targeting SRC and BRAF had an equivalent or better effect on tumor growth inhibition compared to targeting EGFR and BRAF.

    “Their study revealed that targeting SRC and BRAF had an equivalent or better effect on tumor growth inhibition compared to targeting EGFR and BRAF, similar to our observations.”

    From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [45]

  • Ruiz-Saenz et al. showed that SRC plays a major role in adaptive resistance to BRAF inhibition in BRAFV600E CRC.

    “Consistent with our data, the recently published work of Ruiz-Saenz et al. [45] also showed that SRC plays a major role in adaptive resistance to BRAF inhibition in BRAFV600E CRC.”

    From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [45]

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Authors
Ruiz-Saenz, A., Atreya, C. E., Wang, C., Pan, B., Dreyer, C. A., Brunen, D., Prahallad, A., Muñoz, 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., & Coppé, J.-P.
Affiliations
  • University of California, San Francisco (US)
  • The Netherlands Cancer Institute (NL)
  • University of California San Diego (US)
Corresponding author
Coppé, Jean-Philippe
ORCID
Venue
Nature Cancer
Publisher
Springer Science and Business Media LLC
Published
2023-02-09
Volume
4
Issue
2
Pages
240-256
ISSN
2662-1347 (ISSN-L)
DOI
10.1038/s43018-022-00508-5
PMC
PMC9970872
OpenAlex
W4319826248
Cited by
39
References
0
Citations by year
2026: 5 · 2025: 11 · 2024: 15 · 2023: 8
FWCI
4.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
Funders
  • Amgen
  • National Natural Science Foundation of China (81001183)
  • KWF Kankerbestrijding
  • Oncode Institute
  • National Institutes of Health (UL1TR000005)
  • University of California, San Francisco (UL1TR000005)
  • National Cancer Institute (R01CA122216, R01CA229447)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
BRAF V600E mutation, colorectal cancer, Src kinase, COX-2 inhibition, EGFR inhibition, BRAF inhibition, drug resistance, MEK, drug repurposing
MeSH terms
Humans, Colorectal Neoplasms, src-Family Kinases, MAP Kinase Signaling System, Proto-Oncogene Proteins B-raf, Cyclooxygenase 2, ErbB Receptors

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