Profound MEK inhibitor response in a cutaneous melanoma harboring a <em>GOLGA4-RAF1</em> fusion
Abstract
The serine/threonine kinases BRAF and CRAF are critical components of the MAPK signaling pathway that is activated in many cancer types. In approximately 1% of melanomas, BRAF or CRAF is activated through structural arrangements. We describe a metastatic melanoma with a GOLGA4-RAF1 fusion and pathogenic variants in catenin β 1 (CTNNB1) and cyclin-dependent kinase inhibitor 2A (CDKN2A). Anti–cytotoxic T-lymphocyte–associated protein 4/anti–programmed cell death 1 (anti-CTLA4/anti–PD-1) 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 coeffector ETV5, and a high Ki67 index. These findings provide a rationale for the dramatic response to targeted therapy. This study shows that molecular characterization of treatment-resistant cancers can identify therapeutic targets and personalize therapy management, leading to improved patient outcomes.
Acknowledgments
We thank Melbourne Genomic Health Alliances (MGHA) and the Australian Genomic Health Alliance (NHMRC grant 1113531) for funding the I-PREDICT study. We also thank the following individuals at the Peter MacCallum Cancer Centre: Richard Lupat for assistance with GRIDSS (Genome Rearrangement IDentification Software Suite) analysis; Jason Li for setting up the analysis pipeline for the nCounter data set; Jenna Stewart and David Yoannidis for technical assistance; Kelly Waldek for advice on IHC; Chung-Yan Ma for discussions on immunomarkers; and Michael McKay and Glen Gurra for critical discussions of the manuscript.
Funding Statement
No specific Grant number available
Version Changes
Version 1. 03/05/2019
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Version 2. 04/02/2019
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Version 3. 05/01/2019
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Footnotes
Conflict of interest: The authors have declared that no conflict of interest exists.
Copyright: © 2019, The American Society for Clinical Investigation.
Reference information: J Clin Invest. 2019;129(5):1940–1945.https://doi.org/10.1172/JCI123089.
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