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Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.
Nazarian, Ramin 1,2,9; Shi, Hubing 1,2,9; Wang, Qi 1,2; Kong, Xiangju 1,2; Koya, Richard C. 2,3; Lee, Hane 2,4; Chen, Zugen 2,4; Lee, Mi-Kyung 1,2; Attar, Narsis 2,5; Sazegar, Hooman 2,5; Chodon, Thinle 2,5; Nelson, Stanley F. 2,4,6; McArthur, Grant 7; Sosman, Jeffrey A. 8; Ribas, Antoni 2,3,5; Lo, Roger S. 1,2,*
[Letter] Nature. 468(7326):973-977, December 16, 2010.

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: Activating B-RAF(V600E) (also known as BRAF) kinase mutations occur in ~7% of human malignancies and ~60% of melanomas 1. 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 2. 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 3 4 5. Here we show that acquired resistance to PLX4032 develops by mutually exclusive PDGFR[beta] (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 PDGFR[beta] 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. PDGFR[beta]-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 PDGFR[beta] or N-RAS reduced growth of the respective PLX4032-resistant subsets. Overexpression of PDGFR[beta] 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.