CRAF R391W is a melanoma driver oncogene.
Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma. CRAF R391W was homozygous and over expressed. These melanoma cells were highly sensitive to CRAF, but not BRAF knockdown. In reconstitution experiments, CRAF R391W, but not CRAF WT, transformed NIH3T3 cells in soft-agar colony formation assays, increased kinase activity in vitro, induced MAP kinase signaling and conferred vemurafenib resistance. MAP kinase inducing activity was dependent on CRAF dimerization. Thus, CRAF is a bona fide alternative oncogene for BRAF/NRAS/GNAQ/GNA11 wild type melanomas.
Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California (UCLA), 90095, USA.
Mohammad
M
Atefi
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.|Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.
Bjoern
B
Titz
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.|Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.
Jennifer
J
Tsoi
Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California (UCLA), 90095, USA.
Earl
E
Avramis
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.|Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.
Allison
A
Le
New York University, New York, NY 10016, USA.
Charles
C
Ng
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.|Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.
Anastasia
A
Lomova
Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California (UCLA), 90095, USA.
Amanda
A
Lassen
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.|Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.
Michael
M
Friedman
Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California (UCLA), 90095, USA.|New York University, New York, NY 10016, USA.
Bartosz
B
Chmielowski
Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California (UCLA), 90095, USA.|Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.|Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA 90095, USA.|Department of Surgery, Division of Surgical-Oncology, UCLA, Los Angeles, CA 90095, USA.
Antoni
A
Ribas
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.|Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.|New York University, New York, NY 10016, USA.|California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA.
Thomas G
TG
Graeber
D000368:Aged; D000818:Animals; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D041681:NIH 3T3 Cells; D009857:Oncogenes; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*
D019908:Proto-Oncogene Proteins c-raf