Site Editor
Soo Park, MD
Soo Park, MD
Posted: Wednesday, September 10, 2025
The advent of targeted therapeutics such as BRAF and MEK inhibitors has significantly improved outcomes for patients with BRAF V600–mutant melanoma. However, eventual therapeutic resistance remains a considerable obstacle. In a systematic review published in the journal Pharmaceuticals, Cosci et al integrated recent findings from preclinical and clinical studies to identify the molecular mechanisms underlying resistance to BRAF-targeted therapy in patients with melanoma. According to the authors, “Understanding the multifaceted nature of resistance is critical to improving outcomes in advanced melanoma.”
Study Details
The investigators followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to conduct a comprehensive literature search across multiple databases, including MEDLINE/PubMed, EMBASE, and SCOPUS. The search terms “BRAF resistance,” “mechanism,” and “melanoma” were applied to publications up to June 2024, yielding an initial pool of 2,192 records. Three researchers worked methodically and independently to eliminate ineligible or duplicate records and to extract relevant topics from the selected articles.
Key Results
After analysis, 117 articles met the criteria for eligibility. Resistance was categorized into three principal types: primary or intrinsic resistance, which is associated with preexisting genetic alterations that prevent an initial therapeutic response; adaptive resistance, which involves an initial response followed by drug tolerance not due to mutations (often reversible); and acquired resistance, which emerges in an advanced stage and is characterized by drug tolerance caused by mutations (usually irreversible).
A wide range of mechanisms were identified across these categories. These included secondary mutations in genes such as NRAS, NF1, and PTEN; alternative splicing events; and amplification of BRAF itself. Other factors implicated include reactivation of the MAPK and PI3K–AKT pathways, as well as broader transcriptional and epigenetic reprogramming. The tumor microenvironment also emerged as a significant contributor, with stromal interactions and immune evasion strategies playing important roles in resistance to BRAF inhibition.
The review’s authors emphasized that BRAF inhibitors, while effective initially, are insufficient as monotherapy because resistance emerges through multiple, often overlapping mechanisms. As the authors noted, “Primary resistance is linked to preexisting genetic and epigenetic changes that activate alternative signaling pathways, such as PI3K–AKT.”
Several therapeutic tactics have emerged to overcome resistance, with combination approaches receiving particular emphasis. Rational drug combinations, metabolic targeting, and the use of predictive biomarkers were all identified as promising strategies that have the potential to inform future therapeutic developments.
Conclusions
This systematic review provided a detailed synthesis of the complex molecular basis of resistance to BRAF inhibitors in patients with melanoma. By distinguishing between primary, adaptive, and acquired mechanisms, the review highlighted the multifactorial and heterogeneous nature of resistance.
This complexity was recognized by the authors, who concluded, “Overcoming BRAF inhibitor resistance will require moving beyond static interventions and toward a dynamic, systems-level approach to cancer treatment. This includes targeting not only tumor-intrinsic pathways but also the microenvironment and metabolic dependencies and doing so in a way that is responsive to the evolving molecular landscape of each patient’s disease. By embracing this complexity, future melanoma therapies can become more durable, personalized, and aligned with the real-world challenges of clinical oncology.”
Disclosure: For full disclosures of the study authors, visit mdpi.com.
JNCCN Spotlights
Resources
For your Patients
