國家衛生研究院 NHRI:Item 3990099045/10468
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    題名: Overexpressed fatty acid synthase in gastrointestinal stromal tumors: Targeting a progression-associated metabolic driver enhances the antitumor effect of imatinib
    作者: Li, CF;Fang, FM;Chen, YY;Liu, TT;Chan, TC;Yu, SC;Chen, LT;Huang, HY
    貢獻者: National Institute of Cancer Research
    摘要: Purpose: In gastrointestinal stromal tumors (GISTs), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN). Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNA interference or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivo. Results:FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (p<0.0001). FASN overexpression was associated with a nongastric location (p = 0.05), unfavorable genotype (p=0.005), and increased risk level (p<0.001) and independently predicted shorter disease-free survival (p<0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and re-sensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RSP6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT, Ki-67, and phosphorylated PIK3/AKT/mTOR levels and increased TUNEL labeling. Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs.
    日期: 2017-08
    關聯: Clinical Cancer Research. 2017 Aug;23(16):4908-4918.
    Link to: http://dx.doi.org/10.1158/1078-0432.ccr-16-2770
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1078-0432&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000407614400039
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85028058125
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