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Ref Type Journal Article
PMID (39626159)
Authors Simhadri S, Carrick JN, Murphy S, Kothari OA, Al-Hraishami H, Kulkarni A, Jalloul N, Stefanik K, Bandari M, Chettur K, Yao M, Ginjala V, Groisberg R, Hochster H, Mehnert J, Riedlinger G, Khiabanian H, Verzi MP, Tong K, Ganesan S
Title Evolution of Rapid Clonal Dynamics and Non-Cross-Resistance in Response to Alternating Targeted Therapy and Chemotherapy in BRAF-V600E-Mutant Colon Cancer.
Journal Vol Issue Date Pages Journal Short Title
JCO precision oncology 8 2024 Dec e2300260 JCO Precis Oncol
URL
Abstract Text Combined BRAF, MEK, and EGFR inhibition can induce clinical responses in BRAF-V600E-mutant colon cancer, but rapid resistance often occurs.We use serial monitoring of circulating tumor DNA cell-free plasma DNA (cfDNA) in a patient case study in addition to organoids derived from mouse models of BRAF-V600E-mutant intestinal cancer, which emulated the patient's mutational profile to assess drug treatment efficacy.We demonstrate dynamic evolution of resistance to combined EGFR/BRAF/MEK inhibition in a pediatric patient with metastatic BRAF-V600E-mutant, mismatch repair-stable colon cancer. Initial resistance to targeted therapy was associated with development of MET amplification. Sequential treatment with chemotherapy and targeted therapy resulted in clearing of the resistant MET-amplified clone. Rechallenge with combined BRAF/EGFR inhibition resulted in clinical and radiographic response, demonstrating these treatments may be non-cross-resistant. Tumor organoids were used to model clinical findings and demonstrated effectiveness of combined targeted therapy and chemotherapy.These findings suggest rational strategies for combining sequential chemotherapy and BRAF-/EGFR-directed therapy in BRAF-V600E-mutant colon cancer to prevent resistance and improve outcome. The data demonstrate rapid clonal dynamics in response to effective therapies in BRAF-V600E-mutant colon cancer that can be monitored by serial cfDNA analysis. Moreover, in mismatch repair-proficient BRAF-V600E-mutant colon cancers, combined EGFR and BRAF/MEK therapy is not cross-resistant with standard chemotherapy, suggesting new rational combination treatment strategies.

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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 colon cancer sensitive Erlotinib + Fluorouracil + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the addition of Adrucil (fluorouracil) to treatment with the combination of Tarceva (erlotinib) and Zelboraf (vemurafenib) resulted in greater inhibition of viability of mouse colon cancer organoids harboring BRAF V600E in culture compared to Adrucil (fluorouracil) or the doublet combination therapy (PMID: 39626159). 39626159
BRAF V600E colon cancer resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, mouse colon cancer organoids harboring BRAF V600E were resistant to Zelboraf (vemurafenib) in culture (PMID: 39626159). 39626159
BRAF V600E colon cancer predicted - sensitive Dabrafenib + Panitumumab + Trametinib Case Reports/Case Series Actionable In a clinical study, treatment with the combination of Vectibix (panitumumab), Tafinlar (dabrafenib), and Mekinist (trametinib) resulted in a clinical response in a pediatric patient with colon cancer harboring BRAF V600E, as well as TP53 G245S, SMAD4 S504R, and PTEN loss, with decreased liver metastases and reduction in CA-19-9 and BRAF V600E VAF levels in the cell free DNA (PMID: 39626159; NCT02688517). 39626159
BRAF V600E colon cancer sensitive Erlotinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the addition of Tarceva (erlotinib) to treatment with Zelboraf (vemurafenib) inhibited viability of mouse colon cancer organoids harboring BRAF V600E in culture (PMID: 39626159). 39626159