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BRAF fusions identified in melanomas have variable treatment responses and phenotypes

Authors :
Stacey M. Bagby
Betelehem W. Yacob
Jacqueline A. Turner
Judson Bemis
Todd M. Pitts
Robert Van Gulick
Tugs Saikhan Chimed
Richard P Tobin
William A. Robinson
Hannah Lee
Anna Capasso
Kasey L. Couts
John J. Tentler
Martin D. McCarter
Source :
Oncogene. 38:1296-1308
Publication Year :
2018
Publisher :
Springer Science and Business Media LLC, 2018.

Abstract

Oncogenic BRAF fusions have emerged as an alternate mechanism for BRAF activation in melanomas and other cancers. A number of BRAF fusions with different 5' gene partners and BRAF exon breakpoints have been described, but the effects of different partners and breakpoints on cancer phenotypes and treatment responses has not been well characterized. Targeted RNA sequencing was used to screen 60 melanoma patient-derived xenograft (PDX) models for BRAF fusions. We identified three unique BRAF fusions, including a novel SEPT3-BRAF fusion, occurring in four tumors (4/60, 6.7%), all of which were "pan-negative" (lacking other common mutations) (4/18, 22.2%). The BRAF fusion PDX models showed variable growth rates and responses to MAPK inhibitors in vivo. Overexpression of BRAF fusions identified in our study, as well as other BRAF fusions previously identified in melanomas, resulted in a high degree of variability in 2D proliferation and 3D invasion between the different fusions. While exogenously expressed BRAF fusions all responded to MAPK inhibition in vitro, we observed potential differences in signaling and feedback mechanisms. In summary, BRAF fusions are actionable therapeutic targets, however there are significant differences in phenotypes, treatment responses, and signaling which may be clinically relevant.

Details

ISSN :
14765594 and 09509232
Volume :
38
Database :
OpenAIRE
Journal :
Oncogene
Accession number :
edsair.doi...........cfa03962c618067f5101e2dccd98ba99
Full Text :
https://doi.org/10.1038/s41388-018-0514-7