Nilotinib and MEK Inhibitors Induce Synthetic Lethality through Paradoxical Activation of RAF in Drug-Resistant Chronic Myeloid Leukemia

Leisl M. Packer, Sareena Rana, Robert Hayward, Thomas O'Hare, Christopher A. Eide, Ana Rebocho, Sonja Heidorn, Matthew S. Zabriskie, Ion Niculescu-Duvaz, Brian J. Druker, Caroline Springer, Richard Marais

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)715-727
Number of pages13
JournalCancer Cell
Volume20
Issue number6
DOIs
StatePublished - Dec 13 2011

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Nilotinib and MEK Inhibitors Induce Synthetic Lethality through Paradoxical Activation of RAF in Drug-Resistant Chronic Myeloid Leukemia'. Together they form a unique fingerprint.

Cite this