From MAPK Reactivation to Response: Clinical Approaches Targeting BRAF/MEK Resistance in Melanoma

Resistance to BRAF/MEK inhibition remains the central therapeutic challenge in BRAF mutant melanoma. Although combined MAPK-targeted therapy induces rapid and often dramatic tumor responses, most patients ultimately develop progressive disease. Over the past decade, translational studies have fundamentally changed our understanding of this process. Resistance is now recognized not as a single genomic event, but as a biologically heterogeneous and adaptive phenomenon involving tumor cell plasticity, microenvironmental remodeling, and immune evolution. This evolving framework has important clinical implications. Recent randomized sequencing clinical trials have shifted treatment paradigms toward a front-line immune checkpoint blockade for many patients. Similarly, triplet approaches combining MAPK inhibition with immunotherapy have shown heterogenous results on progression-free survival benefit and durable overall survival benefits remain uncertain. At the same time, therapeutic options after progression are rapidly expanding and include ERK inhibitors, next-generation pan-RAF inhibitors, vertical pathway targeting strategies, and emerging approaches directed against persister-cell biology and adaptive resistance states. In this review, we integrate current insights from genomic, transcriptomic, single-cell, and spatial studies with the most relevant clinical trial data to provide a contemporary framework for understanding resistance to MAPK-targeted therapy in melanoma. We further discuss how adaptive monitoring approaches, including circulating tumor DNA analysis, may help guide future biomarker-driven and evolution-informed treatment strategies.Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 1 Given name: [Turkan Ozturk] Last name [Topcu]. Also, kindly confirm the details in the metadata are correct. Please correct Author 1's name designation as follows: Given name: Turkan; Family name: Ozturk Topcu. Please update both the article and the metadata accordingly.Kindly check and confirm whether the organization division, organization name, street and postcode in affilition 3 has been processed correctly and amend if necessary.Corrected.