Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia
Packer, Leisl M., Rana, Sareena, Hayward, Robert, O'Hare, Thomas, Eide, Christopher A., Rebocho, Ana, Heidorn, Sonja, Zabriskie, Matthew S., Niculescu-Duvaz, Ion, Druker, Brian J., Springer, Caroline, & Marais, Richard (2011) Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell, 20(6), pp. 715-727.
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.
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|Item Type:||Journal Article|
|Keywords:||2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3,4 difluorobenzamide; B Raf kinase; dasatinib; imatinib; mitogen activated protein kinase; mitogen activated protein kinase kinase; nilotinib; Ras protein; animal experiment; animal model; article; chronic|
|Subjects:||Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > MEDICAL BIOCHEMISTRY AND METABOLOMICS (110100)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Chemotherapy (111205)
|Divisions:||Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
|Deposited On:||23 Sep 2014 23:07|
|Last Modified:||24 Sep 2014 21:55|
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