Abstract
Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy1,2. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells3,4,5,6,7,8. Thus, using a loss-of-function RNA interference genomic screen, we identified the aberrant expression of hepatocyte growth factor (HGF) as a crucial element in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples we studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance resulting from compensatory upregulation of HGF expression, leading to the restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1)9, concomitant inhibition of FGFR1 and MET blocked this compensatory HGF upregulation, resulting in sustained logarithmic cell killing both in vitro and in xenograft models in vivo. Our results show a widespread dependence of AML cells on autocrine activation of MET, as well as the key role of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers.
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Acknowledgements
We thank A. Gutierrez, M. Mansour and E. Gjini for critical discussions and J. Gilbert for editorial advice. This research was supported by the US National Institutes of Health grant K08CA160660 (A.K.), the William Lawrence and Blanche Hughes Foundation (T.S.), the Samuel Waxman Cancer Research Foundation (J.D.L.), the V Foundation (A.T.L.) and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research (L.M.S.).
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A.K., C.R., K.L.R., T.S., A.C., E.T., V.N. and L.A.M. performed experiments. A.K., S.J.R., P.J.M.V., R.D., J.L.K., S.E.D., R.J.B., J.G.C., G.V.W., J.D.L., A.L.K., L.M.S. and A.T.L. analyzed data. A.K. and A.T.L. wrote the manuscript.
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J.G.C. is an employee of Pfizer.
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Kentsis, A., Reed, C., Rice, K. et al. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat Med 18, 1118–1122 (2012). https://doi.org/10.1038/nm.2819
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DOI: https://doi.org/10.1038/nm.2819
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