Genetic heterogeneity of BRAF fusion kinases in melanoma affects drug responses
Oncogenic BRAF fusions are among the most common kinase rearrangements in cancer and emerge as resistance mechanisms to targeted therapies. However, diversity of fusion partners complicates their detection and guidelines for clinical management are lacking in part due to the scarcity of appropriate model for pre-clinical studies. To help prioritize patient testing, we reviewed clinical cases of melanocytic tumors with BRAF fusions and identified that they are most often associated with female gender and younger age at presentation. We then screened a cohort of patient derived melanoma cell lines with unknown oncogenic drivers and identified six lines harboring BRAF fusions representative of the clinical cases. 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 a RAS-independent paradoxical activation of the MAP-kinase pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, αC-IN/DFG-OUT RAF inhibitors of new generation blunted paradoxical activation across all cell lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors. These findings unveil the singularities of BRAF fusions and establish general principles to guide their clinical management in melanoma and other malignancies.
INSERM U1065, C3M Team 12
Domain 1 - UMR 3347 / U1021 - Normal and pathological signaling
Seminar suggested by Leo Montreer