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

被引:154
作者
Kentsis, Alex [1 ,2 ]
Reed, Casie [1 ,2 ]
Rice, Kim L. [3 ]
Sanda, Takaomi [1 ,2 ]
Rodig, Scott J. [4 ]
Tholouli, Eleni [5 ,6 ]
Christie, Amanda [1 ,2 ,7 ]
Valk, Peter J. M. [8 ]
Delwel, Ruud [8 ]
Vu Ngo [9 ]
Kutok, Jeffery L. [4 ]
Dahlberg, Suzanne E. [10 ]
Moreau, Lisa A. [1 ,2 ]
Byers, Richard J. [5 ,6 ,11 ]
Christensen, James G. [12 ]
Woude, George Vande [13 ]
Licht, Jonathan D. [3 ]
Kung, Andrew L. [1 ,2 ,7 ]
Staudt, Louis M. [14 ]
Look, A. Thomas [1 ,2 ]
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Hematol & Oncol, Boston, MA USA
[3] Northwestern Univ, Feinberg Sch Med, Div Hematol & Oncol, Chicago, IL 60611 USA
[4] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA
[5] Cent Manchester Univ Hosp Natl Hlth Serv Fdn Trus, Manchester Royal Infirm, Dept Haematol, Manchester, Lancs, England
[6] Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England
[7] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA
[8] Erasmus MC, Dept Hematol, Rotterdam, Netherlands
[9] City Hope Natl Med Ctr, Div Hematopoiet Stem Cell & Leukemia Res, Duarte, CA 91010 USA
[10] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA
[11] Univ Manchester, Fac Med & Human Sci, Sch Canc & Enabling Sci, Manchester, Lancs, England
[12] Pfizer Global Res & Dev, Dept Res Pharmacol, La Jolla, CA USA
[13] Van Andel Res Inst, Dept Mol Oncol, Grand Rapids, MI USA
[14] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
基金
美国国家卫生研究院;
关键词
CANCER-CELLS; INHIBITOR; SCREEN; AML; CLASSIFICATION; PATHWAYS; TARGETS; FLT3;
D O I
10.1038/nm.2819
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 chemotherapy(1,2). Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells(3-8). 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.
引用
收藏
页码:1118 / +
页数:7
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