Fatty Acid Synthase Overexpression in Gastrointestinal Stromal Tumor (GIST): Emphasis on Prognostic and Therapeutic Relevance.
Hui-Chun Tai, Chien-Feng Li, Yu-Hui Wang, Chun-Chieh Wu, Hsuan-Ying Huang. Changhua Christian Hospital, Taiwan; Chi-Mei Hosp., Tainan, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan; Institute of Biosignal Transduction, NCKU, Tainan, Taiwan; Kaohsiung Medical University, Taiwan; Chang Gung Memorial Hospital, Kaohsiung, Taiwan
Background: Fatty acid synthase (FASN), a critical enzyme catalyzing synthesis of palmitate into long-chain saturated fatty acids, is frequently overexpressed in a variety of aggressive cancers, including high-risk and metastatic GISTs. In vitro targeting of FASN has shed light on its potential therapeutic application in some carcinomas. However, little is known about the associations of FASN expression in GISTs with clinical outcomes, KIT and PDGFRA receptor tyrosine kinase (RTK) genotypes, and the efficacy of treatment with pharmacological inhibitors.
Design: FASN immunostain was performed on tissue microarrays of primary GISTs, generating 370 cases with interpretable results. Of these, RTK genotypes were determined in 223 GISTs by sequencing with or without screening by DHPLC. FASN mRNA was quantified for 40 independent fresh samples by real-time RT-PCR coupled with laser microdissection. The expression levels of FASN mRNA and immunostain were correlated with clincopathological variables and disease-free survival (DSS). GIST48 and GIST430 cell lines, both imatinib-resistant and FASN-expressing, were subjected to XTT, Western blotting, and caspase-3/7 activity assays to evaluate their susceptibility to FASN inhibitor (Orlistat).
Results: FASN overexpression was present in 100 (27%) GISTs and significantly associated with epithelioid morphology, unfavorable genotypes, larger tumor size, and higher mitotic count, NIH risk category, and Ki-67 labeling index (LI) (all p≤ 0.001). In multivariate analysis, FASN overexpression independently portended inferior DFS (risk ratio [RR]=1.735, p=0.0226), along with intermediate- (RR=2.782) or high-risk (RR=4.816) category (p<0.001), high Ki-67 LI (RR=3.125. p<0.001), non-gastric site (RR=1.930, p=0.008), and unfavorable genotypes (RR=1.763, p=0.0260). The endogenous FASN mRNA expression was significantly more abundant in high-risk GISTs than the non-high-risk counterpart (p=0.0007). In both GIST48 and GIST430 cells, treatment with Orlistat at a concentration of 300 uM could remarkably result in activation of caspases and apparently declined cell viability.
Conclusions: FASN overexpression in GISTs not only confers clinical aggressiveness but also represents a potential alternative therapeutic target in high-risk, imatinib-resistant cases.
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 165, Tuesday Morning