2. Academic Validation
  3. Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer

Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer

  • Br J Cancer. 2025 Aug;133(3):404-419. doi: 10.1038/s41416-025-03058-6.
Beatriz Rubio-Cuesta 1 2,  Carlos Carretero-Puche 1 2,  Patricia Llamas 1 2,  Jacinto Sarmentero 1 2,  Beatriz Gil-Calderon 1 2,  Alberto Lens-Pardo 1 2,  Beatriz Antón-Pascual 1 3,  Eduardo Rubio-González 4,  María Cámara-Jurado 5,  Javier Salamanca 5,  Daniel Rueda-Fernández 6,  Marco Donatello Delcuratolo 1 3,  Beatriz Soldevilla 7 8,  Rocio Garcia-Carbonero 9 10 11 12 13
Affiliations

Affiliations

  • 1 Centro de Oncología Experimental. Grupo de Investigación en Tumores Gastrointestinales y Neuroendocrinos. Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.
  • 2 Centro Nacional de Investigación Oncológica (CNIO), Madrid, Spain.
  • 3 Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 4 Department of General and Digestive Surgery, Hospital Universitario Doce de Octubre, Madrid, Spain.
  • 5 Department of Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 6 Hereditary Cancer Laboratory, 12 de Octubre University Hospital, i + 12 Research Institute, Madrid, Spain.
  • 7 Centro de Oncología Experimental. Grupo de Investigación en Tumores Gastrointestinales y Neuroendocrinos. Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. [email protected].
  • 8 Centro Nacional de Investigación Oncológica (CNIO), Madrid, Spain. [email protected].
  • 9 Centro de Oncología Experimental. Grupo de Investigación en Tumores Gastrointestinales y Neuroendocrinos. Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. [email protected].
  • 10 Centro Nacional de Investigación Oncológica (CNIO), Madrid, Spain. [email protected].
  • 11 Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. [email protected].
  • 12 Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain. [email protected].
  • 13 CIBERONC, Instituto de Salud Carlos III, Madrid, Spain. [email protected].
PMID: 40481178 DOI: 10.1038/s41416-025-03058-6
Abstract

Background: BRAFV600E mutations occur in ∼10% of colorectal Cancer (CRC) patients, leading to poor prognosis. Although BRAF-targeted therapy is ineffective in CRC, adding EGFR inhibitors (EGFRi) improves efficacy, yet patient survival remains suboptimal. This study explores Src as a key mediator of resistance to BRAF inhibitors (BRAFi) in preclinical BRAFV600E CRC models, and its potential as a therapeutic target.

Methods: We studied Src using BRAF-mutated and wild-type CRC cell lines with CRISPR/Cas9 knockouts and lentiviral overexpression. We tested Src, BRAF, EGFR, and JNK targeting drugs, assessing protein expression, cell viability, proliferation, migration, Apoptosis, and cell cycle. CRC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models were established for in vivo studies.

Results: Src regulates proliferation, clonogenicity, migration and mediates BRAFi resistance in BRAFV600E CRC, regardless of microsatellite instability. Depletion or inhibition of Src sensitized cells to BRAFi. Combined Src and BRAF inhibition demonstrated a synergistic antitumor effect, reducing cell viability and inducing Apoptosis and cell cycle arrest in cell lines and PDXs. The JNK/c-Jun pathway contributes to adaptive resistance, and its inhibition enhances the effects of dual Src and BRAF inhibition.

Conclusions: These findings identify new therapeutic targets for clinical trials, potentially improving outcomes for this high-risk CRC subgroup.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15605
    99.93%, BRAF Inhibitor
    Raf