%0 Generic
%A Figueroa Vazquez, Vianihuini
%C Heidelberg
%D 2017
%F heidok:23680
%R 10.11588/heidok.00023680
%T Functional characterizations of BRAF mutations in multiple myeloma
%U https://archiv.ub.uni-heidelberg.de/volltextserver/23680/
%X Activating BRAF mutations are frequently found in diverse types of cancer, including multiple myeloma. Moreover, current targeted therapy can abrogate mutant BRAF kinase activity although drug resistance mechanisms are still a challenge. However, this mutation has not been functionally characterized in multiple myeloma and biological consequences along BRAF inhibitor resistance mechanisms are unknown.    Here we show that BRAF V600E expression in multiple myeloma leads to an active MAPK/ERK pathway and eventual DNA damage. This mutation can be targeted with BRAF inhibitors (BRAFi). Nevertheless, we demonstrate that BRAF wild type under BRAFi leads to paradoxical activation. To overcome this effect a MEK inhibitor was employed for an effective pathway abrogation in multiple myeloma.    Furthermore, to identify mechanisms that contribute to BRAFiresistance, whole exome sequencing of a BRAFi-resistance model of MM was performed. We identified a novel mutation in the transcription factor EGR-1 followed by its protein functional characterization. This showed that the mutant protein (p. 332fs) along the wild type protein is overexpressed in our in vitro model and mutant EGR-1 influences its own subcellular localization. Overexpression of the mutant EGR-1 conferred complete resistance to BRAF inhibition.