BRAF fusions identified in melanomas have variable treatment responses and phenotypes

Jacqueline A. Turner, Judson G.T. Bemis, Stacey M. Bagby, Anna Capasso, Betelehem W. Yacob, Tugs Saikhan Chimed, Robert Van Gulick, Hannah Lee, Richard Tobin, John J. Tentler, Todd Pitts, Martin McCarter, William A. Robinson, Kasey L. Couts

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1296-1308
Number of pages13
JournalOncogene
Volume38
Issue number8
DOIs
StatePublished - Feb 21 2019

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Melanoma
Phenotype
Heterografts
RNA Sequence Analysis
Neoplasms
Exons
Therapeutics
Mutation
Growth
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Turner, J. A., Bemis, J. G. T., Bagby, S. M., Capasso, A., Yacob, B. W., Chimed, T. S., ... Couts, K. L. (2019). BRAF fusions identified in melanomas have variable treatment responses and phenotypes. Oncogene, 38(8), 1296-1308. https://doi.org/10.1038/s41388-018-0514-7

BRAF fusions identified in melanomas have variable treatment responses and phenotypes. / Turner, Jacqueline A.; Bemis, Judson G.T.; Bagby, Stacey M.; Capasso, Anna; Yacob, Betelehem W.; Chimed, Tugs Saikhan; Van Gulick, Robert; Lee, Hannah; Tobin, Richard; Tentler, John J.; Pitts, Todd; McCarter, Martin; Robinson, William A.; Couts, Kasey L.

In: Oncogene, Vol. 38, No. 8, 21.02.2019, p. 1296-1308.

Research output: Contribution to journalArticle

Turner, JA, Bemis, JGT, Bagby, SM, Capasso, A, Yacob, BW, Chimed, TS, Van Gulick, R, Lee, H, Tobin, R, Tentler, JJ, Pitts, T, McCarter, M, Robinson, WA & Couts, KL 2019, 'BRAF fusions identified in melanomas have variable treatment responses and phenotypes', Oncogene, vol. 38, no. 8, pp. 1296-1308. https://doi.org/10.1038/s41388-018-0514-7
Turner, Jacqueline A. ; Bemis, Judson G.T. ; Bagby, Stacey M. ; Capasso, Anna ; Yacob, Betelehem W. ; Chimed, Tugs Saikhan ; Van Gulick, Robert ; Lee, Hannah ; Tobin, Richard ; Tentler, John J. ; Pitts, Todd ; McCarter, Martin ; Robinson, William A. ; Couts, Kasey L. / BRAF fusions identified in melanomas have variable treatment responses and phenotypes. In: Oncogene. 2019 ; Vol. 38, No. 8. pp. 1296-1308.
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