Hepatocyte growth factor renders BRAF mutant human melanoma cell lines resistant to PLX4032 by downregulating the pro-apoptotic BH3-only proteins PUMA and BIM.
A large proportion of melanomas harbour the activating BRAFV600Emutation that renders these cells dependent on MAPK signalling for their survival. Although the highly specific and clinically approved BRAFV600Ekinase 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 member BCL-2 caused no additional cell death. Although the initial response to PLX4032 in melanoma patients is very potent, resistance to the drug eventually develops and relapse occurs. Several factors can cause melanoma cells to develop resistance to PLX4032; one of them is the activation of the receptor tyrosine kinase cMET on melanoma cells by its ligand, hepatocyte growth factor (HGF), provided by the tumour microenvironment or the cancer cells themselves. We found that HGF mediates resistance of cMET-expressing BRAF mutant melanoma cells to PLX4032-induced apoptosis through downregulation of PUMA and BIM rather than by increasing the expression of pro-survival BCL-2-like proteins. These results suggest that resistance to PLX4032 may be overcome by specifically increasing the levels of PUMA and BIM in melanoma cells through alternative signalling cascades or by blocking pro-survival BCL-2 family members with suitable BH3 mimetic compounds.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Leona
L
Rohrbeck
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Jia-Nan
JN
Gong
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.|Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.|Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
Erinna F
EF
Lee
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Andrew J
AJ
Kueh
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
Andreas
A
Behren
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Lin
L
Tai
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Guillaume
G
Lessene
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
David C S
DC
Huang
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.|Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.|Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
Walter D
WD
Fairlie
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Andreas
A
Strasser
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Marco J
MJ
Herold
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D000077484:Vemurafenib; D051020:bcl-X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D000072224:Bcl-2-Like Protein 11; D007211:Indoles; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D051020:bcl-X Protein; D000077484:Vemurafenib; D017228:Hepatocyte Growth Factor; D048493:Proto-Oncogene Proteins B-raf
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