Publication Date:
2010-11-26
Description:
Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in approximately 7% of human malignancies and approximately 60% of melanomas. Early clinical experience with a novel class I RAF-selective inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumour response rate among patients with B-RAF(V600E)-positive melanomas, but acquired drug resistance frequently develops after initial responses. Hypotheses for mechanisms of acquired resistance to B-RAF inhibition include secondary mutations in B-RAF(V600E), MAPK reactivation, and activation of alternative survival pathways. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFRbeta (also known as PDGFRB) upregulation or N-RAS (also known as NRAS) mutations but not through secondary mutations in B-RAF(V600E). We used PLX4032-resistant sub-lines artificially derived from B-RAF(V600E)-positive melanoma cell lines and validated key findings in PLX4032-resistant tumours and tumour-matched, short-term cultures from clinical trial patients. Induction of PDGFRbeta RNA, protein and tyrosine phosphorylation emerged as a dominant feature of acquired PLX4032 resistance in a subset of melanoma sub-lines, patient-derived biopsies and short-term cultures. PDGFRbeta-upregulated tumour cells have low activated RAS levels and, when treated with PLX4032, do not reactivate the MAPK pathway significantly. In another subset, high levels of activated N-RAS resulting from mutations lead to significant MAPK pathway reactivation upon PLX4032 treatment. Knockdown of PDGFRbeta or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFRbeta or N-RAS(Q61K) conferred PLX4032 resistance to PLX4032-sensitive parental cell lines. Importantly, MAPK reactivation predicts MEK inhibitor sensitivity. Thus, melanomas escape B-RAF(V600E) targeting not through secondary B-RAF(V600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143360/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143360/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nazarian, Ramin -- Shi, Hubing -- Wang, Qi -- Kong, Xiangju -- Koya, Richard C -- Lee, Hane -- Chen, Zugen -- Lee, Mi-Kyung -- Attar, Narsis -- Sazegar, Hooman -- Chodon, Thinle -- Nelson, Stanley F -- McArthur, Grant -- Sosman, Jeffrey A -- Ribas, Antoni -- Lo, Roger S -- K22 CA151638/CA/NCI NIH HHS/ -- K22 CA151638-01/CA/NCI NIH HHS/ -- K24 CA097588/CA/NCI NIH HHS/ -- England -- Nature. 2010 Dec 16;468(7326):973-7. doi: 10.1038/nature09626. Epub 2010 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Dermatology/Department of Medicine, UCLA's Jonsson Comprehensive Cancer Center, 52-121 CHS, Los Angeles, California 90095-1750, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107323" target="_blank"〉PubMed〈/a〉
Keywords:
Base Sequence
;
Cell Line, Tumor
;
*Drug Resistance, Neoplasm/drug effects
;
Enzyme Activation/drug effects
;
*Gene Expression Regulation, Neoplastic/drug effects
;
Genes, ras/*genetics
;
Humans
;
Indoles/pharmacology/therapeutic use
;
MAP Kinase Signaling System/drug effects
;
Melanoma/*drug therapy/*enzymology/genetics/pathology
;
Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
;
Mutation/genetics
;
Oligonucleotide Array Sequence Analysis
;
Protein Kinase Inhibitors/pharmacology/therapeutic use
;
Proto-Oncogene Proteins B-raf/*antagonists &
;
inhibitors/chemistry/genetics/metabolism
;
Receptor Protein-Tyrosine Kinases/*metabolism
;
Receptor, Platelet-Derived Growth Factor beta/biosynthesis/genetics
;
Sulfonamides/pharmacology/therapeutic use
;
Up-Regulation/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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