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

2019-05-01

McEvoy, Christopher R

Xu, Huiling

Smith, Kortnye

Etemadmoghadam, Dariush

San Leong, Huei

Choong, David Y

Byrne, David J

Iravani, Amir

Beck, Sophie

Mileshkin, Linda

Tothill, Richard W

Bowtell, David D

Bates, Bindi M

Nastevski, Violeta

Browning, Judy

Bell, Anthony H

Khoo, Chloe

Desai, Jayesh

Fellowes, Andrew P

Fox, Stephen B

Prall, Owen Wj

Cancer

Genetics

Melanoma

Molecular pathology

Oncology

Journal Article

10.1172/JCI123089

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.

link

The Journal of clinical investigation 2019; 129(5): 1940-1945

The Journal of clinical investigation