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Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion
Christopher R. McEvoy, … , Stephen B. Fox, Owen W.J. Prall
Christopher R. McEvoy, … , Stephen B. Fox, Owen W.J. Prall
Published March 5, 2019
Citation Information: J Clin Invest. 2019;129(5):1940-1945. https://doi.org/10.1172/JCI123089.
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Concise Communication Genetics Oncology

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

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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.

Authors

Christopher R. McEvoy, Huiling Xu, Kortnye Smith, Dariush Etemadmoghadam, Huei San Leong, David Y. Choong, David J. Byrne, Amir Iravani, Sophie Beck, Linda Mileshkin, Richard W. Tothill, David D. Bowtell, Bindi M. Bates, Violeta Nastevski, Judy Browning, Anthony H. Bell, Chloe Khoo, Jayesh Desai, Andrew P. Fellowes, Stephen B. Fox, Owen W.J. Prall

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Figure 1

Metastatic melanoma with a GOLGA4-RAF1 fusion.

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Metastatic melanoma with a GOLGA4-RAF1 fusion.
(A) H&E staining of a...
(A) H&E staining of a lymph node metastasis. (B–E) IHC for Melan-A (B), S100 (C), SOX10 (D), and HMB-45 (E). (F) Schematic illustration of the GOLGA4-RAF1 fusion. (G) Sanger sequence of the RT-PCR product. (H) Illustration of previously described GOLGA4-RAF1 fusions showing consistent retention of the RAF1 kinase domain (exons 8–17). Scale bars: 100 μm.

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