Progress and Challenges in Targeting BRAFV600E-mutant Colorectal Cancer: Molecular Pathogenesis, Treatment Strategies, and Future Directions - My Experience at Johns Hopkins University.

Colorectal cancer (CRC) remains a major global health challenge, with the BRAFV600E mutation representing one of the most aggressive and treatment-resistant subtypes. This review focuses on the molecular pathogenesis, clinical implications, and evolving therapeutic strategies for BRAFV600E-mutant CRC. The BRAFV600E mutation leads to constitutive activation of the MAPK signaling pathway, driving tumor proliferation, immune evasion, and resistance to conventional therapies. Despite advances in targeted therapy, including the use of BRAF inhibitors, clinical responses are often short-lived due to feedback activation of EGFR and alternative survival pathways. Combination therapies, such as the BEACON CRC regimen (BRAF, MEK, and EGFR inhibitors), have shown improved outcomes, yet resistance remains a significant obstacle. Our research investigated the potential synergy between BRAF inhibitors, Wnt pathway inhibitors, and epigenetic modifiers, such as DNA methyltransferase (DNMT) inhibitors, in enhancing therapeutic efficacy. Preliminary results suggest that targeting both oncogenic signaling and epigenetic dysregulation may overcome resistance mechanisms in BRAFV600E-mutant CRC. Additionally, we highlight the role of circulating tumor DNA (ctDNA) as a promising biomarker for real-time monitoring of treatment response and clonal evolution. The integration of multi-targeted therapies and liquid biopsy technologies represents a critical step toward precision oncology. Understanding the interplay between genetic mutations, epigenetic alterations, and the tumor microenvironment is essential for developing more durable and personalized treatment strategies. This review outlines current advancements and future directions for managing BRAFV600E-mutant CRC, aiming to improve patient outcomes in this challenging disease subset.