Overexpressed Fatty Acid Synthase in Gastrointestinal Stromal Tumors: Targeting a Progression-Associated Metabolic Driver Enhances the Antitumor Effect of Imatinib.

Abstract

<b>Purpose:</b> In gastrointestinal stromal tumors (GIST), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN).<b>Experimental Design:</b> Forty GISTs were quantitated for <i>FASN</i> mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known <i>KIT/PDGFRA/BRAF</i> genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, <i>KIT</i> transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNAi or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated <i>in vivo</i><b>Results:</b><i>FASN</i> mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (<i>P</i> < 0.0001). FASN overexpression was associated with a nongastric location (<i>P</i> = 0.05), unfavorable genotype (<i>P</i> = 0.005), and increased risk level (<i>P</i> < 0.001) and independently predicted shorter disease-free survival (<i>P</i> < 0.001). <i>In vitro</i>, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and resensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the <i>KIT</i> promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RPS6/4E-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 phosphorylation, Ki-67, and phosphorylated PI3K/AKT/mTOR levels and increased TUNEL labeling.<b>Conclusions:</b> We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses <i>KIT</i> transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs. <i>Clin Cancer Res; 23(16); 4908-18. ©2017 AACR</i>.