Beyond BRAF V600: emerging MAPK-targeted therapeutic strategies
- 1Department of Medical Oncology, Instituto Oncologico Dr Rosell, Dexeus University Hospital, Barcelona, Spain
- 2Department of Medical Oncology, Institut Català d’Oncologia, ICO-Badalona, H. Germans Trias i Pujol, Badalona, Spain
- 3Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain
Abstract
Melanoma remains one of the examples of precision oncology, with targeted therapies improving outcomes in patients harboring BRAF V600 mutations. However, approximately 30% to 40% of melanomas are driven by other alterations affecting the mitogen-activated protein kinase (MAPK) pathway, particularly NRAS mutations in 20% and NF1 loss in 10% of cases, for which no targeted therapy has been developed. The limited efficacy of MEK inhibition and the intrinsic biological complexity of RAS-driven tumors have highlighted the need for innovative therapeutic strategies capable of overcoming adaptive signaling and RAF dimer-dependent activation. A deeper understanding of RAF biology has fundamentally changed the development of MAPK inhibitors. Recognition that RAF proteins signal as monomers or dimers depending on the oncogenic context has led to the emergence of several next-generation therapeutic approaches extending far beyond conventional BRAF inhibition. Type II pan-RAF inhibitors capable of targeting RAF dimers, paradox-breaking BRAF inhibitors (BRAFi), RAF degraders, RAF-MEK molecular glues, RAF-MEK clamp inhibitors, and tri-complex RAS inhibitors are promising therapeutic opportunities for tumors driven by NRAS, non-V600 BRAF, NF1, V600 BRAF-resistant tumors and other MAPK pathway alterations. Among these approaches, selective pan-RAF inhibitors have demonstrated encouraging clinical activity in NRAS-mutant melanoma and non-V600 BRAF, while entirely novel concepts, including molecular glues that stabilize inactive RAF-MEK complexes and RAS-directed tri-complex inhibitors, have shown broad preclinical activity across multiple MAPK-dependent malignancies. At the same time, increasing knowledge of adaptive resistance mechanisms involving ARAF, KSR proteins, focal adhesion kinase (FAK), YAP signaling, SOS1 activation, and metabolic vulnerabilities is opening new avenues for rational combination strategies. This review summarizes recent advances in MAPK-targeted drug development beyond classical BRAFi, emphasizing the biological rationale underlying these emerging therapeutic classes, available clinical evidence, mechanisms of resistance, and future directions for precision treatment of patients with advanced melanoma. Collectively, these developments suggest that the next generation of MAPK inhibitors may finally overcome one of the therapeutic challenges in melanoma.
Related
- Targeted Protein Degradation: From Molecular Mechanisms to Emerging Therapeutic Strategies.
- Mitochondrial Dysfunction in Neurodegenerative Diseases: Molecular Mechanisms, Primary Drivers Versus Early Amplifiers, and Emerging Mitochondria-Targeted Therapeutic Strategies
- The Role of Neutrophil Extracellular Traps (NETosis) in Systemic Lupus Erythematosus: Molecular Mechanisms, Pathogenic Roles, Diagnostic Biomarkers, and Emerging Therapeutic Strategies
- Beyond Targeted Delivery: The Emerging Immunomodulatory Landscape of Antibody-Oligonucleotide Conjugates
- β-Catenin Signaling in Hepatocellular Carcinoma: Mechanisms of Therapeutic Resistance and Emerging Therapeutic Strategies.
BibTeX
@article{gonzalezcao2026beyond,
title = {{Beyond BRAF V600: emerging MAPK-targeted therapeutic strategies}},
author = {Maria Gonzalez-Cao and José Luis Manzano and Teresa Puértolas and Jorge Gonzales and Rafael Rosell},
journal = {Annals of Translational Medicine},
year = {2026},
month = oct,
doi = {10.21037/atm-2026-0157},
url = {https://doi.org/10.21037/atm-2026-0157},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Beyond BRAF V600: emerging MAPK-targeted therapeutic strategies
AU - Maria Gonzalez-Cao
AU - José Luis Manzano
AU - Teresa Puértolas
AU - Jorge Gonzales
AU - Rafael Rosell
PY - 2026
DA - 2026/10/23
JO - Annals of Translational Medicine
DO - 10.21037/atm-2026-0157
UR - https://doi.org/10.21037/atm-2026-0157
AB - Melanoma remains one of the examples of precision oncology, with targeted therapies improving outcomes in patients harboring BRAF V600 mutations. However, approximately 30% to 40% of melanomas are driven by other alterations affecting the mitogen-activated protein kinase (MAPK) pathway, particularly NRAS mutations in 20% and NF1 loss in 10% of cases, for which no targeted therapy has been developed. The limited efficacy of MEK inhibition and the intrinsic biological complexity of RAS-driven tumors have highlighted the need for innovative therapeutic strategies capable of overcoming adaptive signaling and RAF dimer-dependent activation. A deeper understanding of RAF biology has fundamentally changed the development of MAPK inhibitors. Recognition that RAF proteins signal as monomers or dimers depending on the oncogenic context has led to the emergence of several next-generation therapeutic approaches extending far beyond conventional BRAF inhibition. Type II pan-RAF inhibitors capable of targeting RAF dimers, paradox-breaking BRAF inhibitors (BRAFi), RAF degraders, RAF-MEK molecular glues, RAF-MEK clamp inhibitors, and tri-complex RAS inhibitors are promising therapeutic opportunities for tumors driven by NRAS, non-V600 BRAF, NF1, V600 BRAF-resistant tumors and other MAPK pathway alterations. Among these approaches, selective pan-RAF inhibitors have demonstrated encouraging clinical activity in NRAS-mutant melanoma and non-V600 BRAF, while entirely novel concepts, including molecular glues that stabilize inactive RAF-MEK complexes and RAS-directed tri-complex inhibitors, have shown broad preclinical activity across multiple MAPK-dependent malignancies. At the same time, increasing knowledge of adaptive resistance mechanisms involving ARAF, KSR proteins, focal adhesion kinase (FAK), YAP signaling, SOS1 activation, and metabolic vulnerabilities is opening new avenues for rational combination strategies. This review summarizes recent advances in MAPK-targeted drug development beyond classical BRAFi, emphasizing the biological rationale underlying these emerging therapeutic classes, available clinical evidence, mechanisms of resistance, and future directions for precision treatment of patients with advanced melanoma. Collectively, these developments suggest that the next generation of MAPK inhibitors may finally overcome one of the therapeutic challenges in melanoma.
SN - 2305-5839
SN - 2305-5847
ER -