BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation aC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions.
Authors | Botton, Thomas; Talevich, Eric; Mishra, Vivek Kumar; Zhang, Tongwu; Shain, A Hunter; Berquet, Céline; Gagnon, Alexander; Judson, Robert L; Ballotti, Robert; Ribas, Antoni; Herlyn, Meenhard; Rocchi, Stéphane; Brown, Kevin M; Hayward, Nicholas K; Yeh, Iwei; Bastian, Boris C |
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Journal | Cell Reports |
Pages | 573-588.e7 |
Volume | 29 |
Date | 1/10/2019 |
Grant ID | K22 CA217997 |
Funding Body | NCI NIH HHS |
URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016/j.celrep.2019.09.009 |