Breaking resistance in BRAF-mutant Melanoma: Novel strategies and biomarkers for optimizing targeted therapies.

In metastatic melanoma with a BRAFV600 mutation, inhibitors of BRAF and MEK have improved survival. Resistance may be acquired through late genetic alterations that restore mitogen-activated protein kinase (MAPK) signaling. Resistance can also be adaptive, involving early and reversible transcriptional or metabolic shifts that generate drug-tolerant cells, or intrinsic, arising from pre-existing conditions such as phosphatase and tensin homolog (PTEN) loss or an AXL receptor tyrosine kinase-high (AXL-high) state. For instance, some tumors exhibit phenotypic plasticity, dynamically switching between AXL-high invasive and microphthalmia-associated transcription factor-high (MITF-high) proliferative cell states, leading to relapse after an initial response. When compared to upfront targeted therapy, first-line immune checkpoint blockades typically confer greater long-term survival, according to major clinical trials examining therapeutic sequencing (DREAMseq, SECOMBIT, EBIN). BRAF and MEK inhibitors remain effective when used as second-line therapy, and high-risk patients can safely achieve quick tumor control without sacrificing results by receiving a brief course of targeted therapy prior to immunotherapy. To enable precision-guided adaptive dosage, (ctDNA) has emerged as a valuable biomarker for early detection of resistance mutations and real-time monitoring of disease dynamics. The article concludes that new investigational approaches to overcoming resistance include triplet regimens (targeted therapy plus immunotherapy), co-targeting alternative pathways (such as AXL receptor tyrosine kinase-high (AXL) or phosphoinositide 3-kinase-AKT (PI3K-AKT)), and incorporating radiotherapy to eradicate resistant clones. However, strategies such as intermittent (adaptive) dosing have failed to improve outcomes in clinical trials. Ongoing trials and advances in artificial intelligence-driven personalization may further refine treatment selection and improve long-term outcomes.