TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition.
Specific chromosomal translocations encoding chimeric transcription factors are considered to play crucial oncogenic roles in a variety of human cancers but the fusion proteins themselves seldom represent suitable therapeutic targets. Oncogenic TFE3 fusion proteins define a subset of pediatric renal adenocarcinomas and one fusion (ASPL-TFE3) is also characteristic of alveolar soft part sarcoma (ASPS). By expression profiling, we identified the MET receptor tyrosine kinase gene as significantly overexpressed in ASPS relative to four other types of primitive sarcomas. We therefore examined MET as a direct transcriptional target of ASPL-TFE3. ASPL-TFE3 binds to the MET promoter and strongly activates it. Likewise, PSF-TFE3 and NONO-TFE3 also bind this promoter. Induction of MET by ASPL-TFE3 results in strong MET autophosphorylation and activation of downstream signaling in the presence of hepatocyte growth factor (HGF). In cancer cell lines containing endogenous TFE3 fusion proteins, inhibiting MET by RNA interference or by the inhibitor PHA665752 abolishes HGF-dependent MET activation, causing decreased cell growth and loss of HGF-dependent phenotypes. MET is thus a potential therapeutic target in these cancers. Aberrant transcriptional up-regulation of MET by oncogenic TFE3 fusion proteins represents another mechanism by which certain cancers become dependent on MET signaling. The identification of kinase signaling pathways transcriptionally up-regulated by oncogenic fusion proteins may reveal more accessible therapeutic targets in this class of human cancers.
Tsuda
Masumi
M
Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Davis
Ian J
IJ
Argani
Pedram
P
Shukla
Neerav
N
McGill
Gael G
GG
Nagai
Makoto
M
Saito
Tsuyoshi
T
Laé
Marick
M
Fisher
David E
DE
Ladanyi
Marc
M
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D014158:Transcription, Genetic; D015854:Up-Regulation
C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D007211:Indoles; D015514:Oncogene Proteins, Fusion; D013450:Sulfones; C069203:TFE3 protein, human; D019859:Proto-Oncogene Proteins c-met