Abstract
Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.
Publication types
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Clinical Trial, Phase I
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Clinical Trial, Phase II
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Antineoplastic Agents / therapeutic use
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Drug Resistance, Neoplasm / physiology*
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Humans
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Imidazoles / therapeutic use
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Male
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Melanoma / drug therapy
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Melanoma / genetics*
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Melanoma / metabolism
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Middle Aged
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Oximes / therapeutic use
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors
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Proto-Oncogene Proteins B-raf / genetics*
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Pyridones / therapeutic use
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Pyrimidinones / therapeutic use
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Signal Transduction
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Skin Neoplasms / drug therapy
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Skin Neoplasms / genetics*
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Skin Neoplasms / metabolism
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raf Kinases / antagonists & inhibitors
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raf Kinases / genetics
Substances
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Antineoplastic Agents
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Imidazoles
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Oximes
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Protein Kinase Inhibitors
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Pyridones
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Pyrimidinones
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trametinib
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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raf Kinases
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Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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dabrafenib