Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia

Cancer Cell. 2011 Dec 13;20(6):715-27. doi: 10.1016/j.ccr.2011.11.004.

Abstract

We show that imatinib, nilotinib, and dasatinib possess weak off-target activity against RAF and, therefore, drive paradoxical activation of BRAF and CRAF in a RAS-dependent manner. Critically, because RAS is activated by BCR-ABL, in drug-resistant chronic myeloid leukemia (CML) cells, RAS activity persists in the presence of these drugs, driving paradoxical activation of BRAF, CRAF, MEK, and ERK, and leading to an unexpected dependency on the pathway. Consequently, nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice. Thus, we show that imatinib, nilotinib, and dasatinib drive paradoxical RAF/MEK/ERK pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use
  • Cell Line, Tumor
  • Dasatinib
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Enzyme Activation / drug effects*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Genes, ras
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System
  • Mice
  • Mice, Nude
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Thiazoles / pharmacology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • raf Kinases / metabolism*

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Thiazoles
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • Dasatinib