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Ref Type Journal Article
PMID (40481178)
Authors Rubio-Cuesta B, Carretero-Puche C, Llamas P, Sarmentero J, Gil-Calderon B, Lens-Pardo A, Antón-Pascual B, Rubio-González E, Cámara-Jurado M, Salamanca J, Rueda-Fernández D, Delcuratolo MD, Soldevilla B, Garcia-Carbonero R
Title Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer.
Journal Vol Issue Date Pages Journal Short Title
British journal of cancer 133 3 2025 Aug 404-419 Br J Cancer
URL
Abstract Text 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.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.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.These findings identify new therapeutic targets for clinical trials, potentially improving outcomes for this high-risk CRC subgroup.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colorectal cancer sensitive Dasatinib + Encorafenib Preclinical - Pdx & cell culture Actionable In a preclinical study, treatment with the combination of Braftovi (encorafenib) and Sprycel (dasatinib) induced apoptosis and cell cycle arrest, inhibited colony formation and migration, and synergistically inhibited viability in colorectal cancer cell lines harboring BRAF V600E in culture and increased tumor growth inhibition in cell line and patient-derived xenograft (PDX) models compared to either drug alone (PMID: 40481178). 40481178
BRAF V600E colorectal cancer sensitive Dasatinib + Vemurafenib Preclinical - Pdx & cell culture Actionable In a preclinical study, treatment with the combination of Zelboraf (vemurafenib) and Sprycel (dasatinib) induced apoptosis and cell cycle arrest, inhibited colony formation and migration, and synergistically inhibited viability in colorectal cancer cell lines harboring BRAF V600E in culture and increased tumor growth inhibition in cell line and patient-derived xenograft (PDX) models compared to either drug alone (PMID: 40481178). 40481178