Genetic Heterogeneity of BRAF Fusion Kinases in Melanoma Affects Drug Responses
Thomas Botton,
Eric Talevich,
Vivek Kumar Mishra,
Tongwu Zhang,
A. Hunter Shain,
Céline Berquet,
Alexander Gagnon,
Robert L. Judson,
Robert Ballotti,
Antoni Ribas,
Meenhard Herlyn,
Stéphane Rocchi,
Kevin M. Brown,
Nicholas K. Hayward,
Iwei Yeh,
Boris C. Bastian
Affiliations
Thomas Botton
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA; Corresponding author
Eric Talevich
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
Vivek Kumar Mishra
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
Tongwu Zhang
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MA 20892, USA
A. Hunter Shain
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
Céline Berquet
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
Alexander Gagnon
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
Robert L. Judson
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA
Robert Ballotti
U1065, Institut National de la Santé et de la Recherche Médicale, Centre Méditerranéen de Médecine Moléculaire, Université Côte d’Azur, 06200 Nice, France
Antoni Ribas
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA
Meenhard Herlyn
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA
Stéphane Rocchi
U1065, Institut National de la Santé et de la Recherche Médicale, Centre Méditerranéen de Médecine Moléculaire, Université Côte d’Azur, 06200 Nice, France
Kevin M. Brown
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MA 20892, USA
Nicholas K. Hayward
Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
Iwei Yeh
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA
Boris C. Bastian
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA; Corresponding author
Summary: 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. : 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. Keywords: BRAF fusion, melanoma, paradoxical activation, RAF inhibitor, MEK inhibitor, sequencing, rearrangement, translocation, kinase, pre-clinical
