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.
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
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. We reserve the right to edit any letter for length, content, and clarity. Authors will be notified by e-mail if their letters were accepted. No appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at firstname.lastname@example.org.