Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion

J Clin Invest. 2019 May 1;129(5):1940-1945. doi: 10.1172/JCI123089. Epub 2019 Mar 5.


BRAF and CRAF are critical components of the MAPK signaling pathway which is activated in many cancer types. In approximately 1% of melanomas, BRAF or CRAF are activated through structural arrangements. We describe here a metastatic melanoma with a GOLGA4-RAF1 fusion and pathogenic variants in CTNNB1 and CDKN2A. Anti-CTLA4/anti-PD1 combination immunotherapy failed to control tumor progression. In the absence of other actionable variants the patient was administered MEK inhibitor therapy on the basis of its potential action against RAF1 fusions. This resulted in a profound and clinically significant response. We demonstrated that GOLGA4-RAF1 expression was associated with ERK activation, elevated expression of the RAS/RAF downstream co-effector ETV5, and a high Ki67 index. These findings provide a rationale for the dramatic response to targeted therapy. This study shows that thorough molecular characterization of treatment-resistant cancers can identify therapeutic targets and personalize management, leading to improved patient outcomes.

Keywords: Cancer; Genetics; Melanoma; Molecular pathology; Oncology.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Autoantigens / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fluorodeoxyglucose F18 / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • Male
  • Melanoma / genetics*
  • Neoplasm Metastasis
  • Oncogene Proteins, Fusion / metabolism
  • Positron-Emission Tomography
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-raf / genetics*
  • Skin Neoplasms / genetics*
  • beta Catenin / metabolism


  • Autoantigens
  • CDKN2A protein, human
  • CTNNB1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • GOLGA4 protein, human
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • beta Catenin
  • Fluorodeoxyglucose F18
  • Proto-Oncogene Proteins c-raf
  • Raf1 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1

Grants and funding

No specific Grant number available