Genetic Heterogeneity of BRAF Fusion Kinases in Melanoma Affects Drug Responses

• Published in: Cell reports (Cambridge) Vol. 29; no. 3; pp. 573 - 588.e7
• Main 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2019; Elsevier
• Subjects: Animals; BRAF fusion; Dimerization; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Intracellular Signaling Peptides and Proteins - genetics; kinase; MEK inhibitor; melanoma; Melanoma - genetics; Melanoma - pathology; Mice; Mice, Nude; Mitogen-Activated Protein Kinases - metabolism; Oncogene Proteins, Fusion - antagonists & inhibitors; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; paradoxical activation; pre-clinical; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - genetics; RAF inhibitor; ras Proteins - genetics; ras Proteins - metabolism; rearrangement; RNA Interference; RNA, Small Interfering - metabolism; sequencing; Signal Transduction; translocation; Vemurafenib - pharmacology; paradoxical activation; kinase; translocation; BRAF fusion; melanoma; RAF inhibitor; MEK inhibitor; rearrangement; sequencing; pre-clinical
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.09.009

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 αC-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. [Display omitted] •BRAF fusions of melanocytic tumors are associated with younger age and female gender•Numerous fusion partners exist with variations in signaling and drug response•Fusion partners alter drug responses via dimerization and expression levels•Next-generation RAF inhibitors are most effective and synergize with MEK inhibitors Botton et al. shed light on the heterogeneity of BRAF fusions encountered in melanocytic tumors and characterize features influencing their signaling and drug response. These findings unveil the singularities of BRAF fusions and establish general principles to guide their clinical management in melanoma and other malignancies.