TY - JOUR
T1 - Nilotinib and MEK Inhibitors Induce Synthetic Lethality through Paradoxical Activation of RAF in Drug-Resistant Chronic Myeloid Leukemia
AU - Packer, Leisl M.
AU - Rana, Sareena
AU - Hayward, Robert
AU - O'Hare, Thomas
AU - Eide, Christopher A.
AU - Rebocho, Ana
AU - Heidorn, Sonja
AU - Zabriskie, Matthew S.
AU - Niculescu-Duvaz, Ion
AU - Druker, Brian J.
AU - Springer, Caroline
AU - Marais, Richard
N1 - Funding Information:
This work was supported by a Training Fellowship from The Harry J Lloyd Charitable Trust (to L.M.P.), Cancer Research UK (ref: C107/A10433 and C309/A2187), and The Institute of Cancer Research. We are grateful to Dr. Nicholas Donato for providing the BV173, BV173R, and K562R cells. B.J.D. is currently the principal investigator on Novartis and Bristol-Myers Squibb clinical trials. His institution has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead. He does not derive salary, nor does his lab receive funds from these contracts.
PY - 2011/12/13
Y1 - 2011/12/13
N2 - 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.
AB - 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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U2 - 10.1016/j.ccr.2011.11.004
DO - 10.1016/j.ccr.2011.11.004
M3 - Article
C2 - 22169110
AN - SCOPUS:83555174377
SN - 1535-6108
VL - 20
SP - 715
EP - 727
JO - Cancer Cell
JF - Cancer Cell
IS - 6
ER -