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 chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells. 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), 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.
journal_name
Nat Medjournal_title
Nature medicineauthors
Kentsis A,Reed C,Rice KL,Sanda T,Rodig SJ,Tholouli E,Christie A,Valk PJ,Delwel R,Ngo V,Kutok JL,Dahlberg SE,Moreau LA,Byers RJ,Christensen JG,Vande Woude G,Licht JD,Kung AL,Staudt LM,Look ATdoi
10.1038/nm.2819subject
Has Abstractpub_date
2012-07-01 00:00:00pages
1118-22issue
7eissn
1078-8956issn
1546-170Xpii
nm.2819journal_volume
18pub_type
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