Abstract 5094: Mutant specific mitochondrial localization of BRAFV600E: Clinically used BRAF kinase inhibitors are not able to block mitochondrial actions of BRAFV600E
Min Hee Lee, Koon Soon Kim, Seong Eun Lee, Min Jeong Ryu, Soung Joong Kim, Yong Kyoung Kim, Gi Ryang Kweon, Young Suk Jo, Minho Shong · Cancer Research · 2010
Abstract Oncogenic mutation in BRAF kinase (BRAFV600E) results active structural conformation characterized with greatly elevated ERK activities. However, other cellular effects which are specifically influenced by mutation in BRAF kinase remains to be identified. We investigated differences in subcellular localizations of wild type and mutant BRAFV600E and observed the effects of the BRAF inhibitors on subcellular compartment-specific effects of BRAFV600E. We found that significant portion of endogenous and exogenous BRAFV600E, but not wild type BRAF, was detected in mitochondrial fraction. The other BRAF mutants, BRAFV600D, BRAFV600K and BRAFV600R which shows higher kinase activities were able to localize in mitochondria. The localization of BRAFV600E onto mitochondria provides anti-apoptotic activities against staurosporine and TNFα/cycloheximide. In addition, inducible expression of BRAFV600E increases glucose uptake rate, decreased O2 consumption, suggesting reduced mitochondrial oxidative phosphorylation which are signature features found in cancer cells. Interestingly, suppression of MEK activities using U0126 did not affect both mitochondrial localization and anti-apoptotic activities of BRAFV600E. The BRAF inhibitor such as Sorafenib was effective to inhibit MEK/ERK activation, however, they did not block the mitochondrial localization of BRAFV600E. Therefore, these inhibitors did not block the antiapoptotic activities and not reduce high glucose uptake rate and glycolytic activities induced by BRAFV600E. We found oncogenic BRAF mutants are able to localize in mitochondria and these actions might be related to altered responses to apoptotic stimuli and to characteristic metabolic phenotypes. In addition, currently BRAFV600E inhibitors were not sufficient to block mitochondrial localization of BRAFV600E and it may explain the limited efficacy of these drugs in clinically advanced BRAFV600E-positive tumors. These observations provide new mutation- specific roles of BRAFV600E which is potentially important for the development of therapeutics. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5094.