Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia

Nature Medicine volume 18, pages1118–1122(2012)Cite this article

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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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Figure 1: Aberrant HGF expression by AML cells is associated with MET activation and is necessary for cell growth and survival.
Figure 2: HGF and MET are coexpressed in the leukemic blasts of patients with AML and are induced by leukemogenic transcription factors in primary mouse hematopoietic progenitor cells, conferring susceptibility to MET kinase inhibition.
Figure 3: Restoration of leukemic cell growth after chronic MET kinase inhibitor treatment is a result of the compensatory upregulation of HGF and MET reactivation, which can be overcome by inhibiting the compensatory upregulation of HGF.
Figure 4: Combined inhibition of MET and FGFR1 blocks the compensatory upregulation of HGF, leading to sustained inhibition of MET in KG-1 cells and near-complete regression of AML in vivo.

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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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Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Alex Kentsis, Casie Reed, Takaomi Sanda, Amanda Christie, Lisa A Moreau, Andrew L Kung & A Thomas Look

  2. Division of Hematology and Oncology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA

    Alex Kentsis, Casie Reed, Takaomi Sanda, Amanda Christie, Lisa A Moreau, Andrew L Kung & A Thomas Look

  3. Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Kim L Rice & Jonathan D Licht

  4. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Scott J Rodig & Jeffery L Kutok

  5. Department of Haematology, Manchester Royal Infirmary, Central Manchester University Hospitals National Health Service Foundation Trust, and Manchester Academic Health Science Centre, Manchester, UK

    Eleni Tholouli & Richard J Byers

  6. Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Amanda Christie & Andrew L Kung

  7. Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands

    Peter J M Valk & Ruud Delwel

  8. Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, California, USA

    Vu Ngo

  9. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Suzanne E Dahlberg

  10. School of Cancer and Enabling Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

    Richard J Byers

  11. Department of Research Pharmacology, Pfizer Global Research and Development, La Jolla, California, USA

    James G Christensen

  12. Department of Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan, USA

    George Vande Woude

  13. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Louis M Staudt

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  1. Alex Kentsis
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Contributions

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.

Corresponding author

Correspondence to A Thomas Look.

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J.G.C. is an employee of Pfizer.

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Supplementary Figures 1–19, Supplementary Tables 1–3 and Supplementary Methods (PDF 2513 kb)

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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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