RT Journal Article
SR Electronic
T1 Melanomagenesis driven by a kinase-dead mutant BRAF lacking codons 600-618
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.20.457149
DO 10.1101/2021.08.20.457149
A1 Megan A. Girtman
A1 Craig S. Richmond
A1 Meagan E. Campbell
A1 William M. Rehrauer
A1 Paraic A. Kenny
YR 2021
UL http://biorxiv.org/content/early/2021/08/20/2021.08.20.457149.abstract
AB While considerable success has been achieved with treating BRAF-V600E mutant tumors in several organ systems, tumors expressing non-V600E BRAF mutations remain a significant clinical challenge. Such atypical BRAF mutations are classified based on their kinase activity, RAS-dependence and their requirement for dimerization to function. We identified an unusually large in-frame deletion in a melanoma patient, encompassing codons 600-618 in the kinase domain. This patient experienced rapid disease progression when treated with dual BRAF/MEK inhibition. To determine whether and how such a large in-frame BRAF deletion might be activating, we ectopically expressed it in HEK293 cells and monitored BRAF pathway activation and response to BRAF and MEK inhibitors. We demonstrate that this mutation results in a kinase-deficient BRAF mutant which, nevertheless, activates MEK/ERK signaling in a dimerization-dependent manner, placing this mutation among the class III BRAF mutants.Competing Interest StatementThe authors have declared no competing interest.