Ontology highlight
ABSTRACT:
SUBMITTER: Packer LM
PROVIDER: S-EPMC3951999 | biostudies-literature | 2011 Dec
REPOSITORIES: biostudies-literature
Packer Leisl M LM Rana Sareena S Hayward Robert R O'Hare Thomas T Eide Christopher A CA Rebocho Ana A Heidorn Sonja S Zabriskie Matthew S MS Niculescu-Duvaz Ion I Druker Brian J BJ Springer Caroline C Marais Richard R
Cancer cell 20111201 6
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 ...[more]