Journal article
Hepatocyte growth factor renders BRAF mutant human melanoma cell lines resistant to PLX4032 by downregulating the pro-apoptotic BH3-only proteins PUMA and BIM
L Rohrbeck, JN Gong, EF Lee, AJ Kueh, A Behren, L Tai, G Lessene, DCS Huang, WD Fairlie, A Strasser, MJ Herold
Cell Death and Differentiation | Published : 2016
DOI: 10.1038/cdd.2016.96
Abstract
A large proportion of melanomas harbour the activating BRAF V600E mutation that renders these cells dependent on MAPK signalling for their survival. Although the highly specific and clinically approved BRAF V600E kinase inhibitor, PLX4032, induces apoptosis of melanoma cells bearing this mutation, the underlying molecular mechanisms are not fully understood. Here, we reveal that PLX4032-induced apoptosis depends on the induction of the pro-apoptotic BH3-only protein PUMA with a minor contribution of its relative BIM. Apoptosis could be significantly augmented when PLX4032 was combined with an inhibitor of the pro-survival protein BCL-XL, whereas neutralization of the pro-survival family memb..
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Awarded by Leukemia and Lymphoma Society
Funding Acknowledgements
We thank all members of the MJ Herold laboratory as well as Drs. ARD Delbridge, B Aubrey, S Grabow and Ms. T Harris for their support and advice; Drs. JM Adams and ARD Delbridge for comments on the article; Drs. L O'Connor, L Milla and S Wilcox for help with the interpretation of sequencing results; and Dr. S Monard and his team for help with flow cytometry. This work was supported by the Melbourne International Research Scholarship and the Melbourne International Fee Remission Scholarship (to LR), the Australian Cancer Research Foundation, the National Health and Medical Research Council, Australia program grant 1016701 and fellowship 1020363, Leukemia and Lymphoma Society SCOR grant 7001-13 (to AS) and grants 7015 and 7413 (to GL), project grant GNT1049720 (to MJH) and GNT1025138 (to GL) a Worldwide Cancer Research Grant 15-0025 (to WDF, MJH, EFL, AS) and Australian Research Council Future Fellowship FR150100212 (to EFL). This work was made possible through Victoria State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme.