Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer

Abstract

// Yekaterina Y. Zaytseva 1 , Piotr G. Rychahou 2, 3 , Anh-Thu Le 3 , Timothy L. Scott 4 , Robert M. Flight 4 , Ji Tae Kim 2 , Jennifer Harris 3 , Jinpeng Liu 2 , Chi Wang 2 , Andrew J. Morris 5 , Theru A. Sivakumaran 2 , Teresa Fan 4 , Hunter Moseley 4 , Tianyan Gao 2 , Eun Y. Lee 6 , Heidi L. Weiss 2 , Timothy S. Heuer 7 , George Kemble 7 and Mark Evers 2, 3 1 Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA 2 Markey Cancer Center, University of Kentucky, Lexington, KY, USA 3 Department of Surgery, University of Kentucky, Lexington, KY, USA 4 RC-SIRM, University of Kentucky, Lexington, KY, USA 5 Cardiovascular Research, University of Kentucky, Lexington, KY, USA 6 Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA 7 3-V Biosciences, Menlo Park, CA, USA Correspondence to: Yekaterina Y. Zaytseva, email: yyzayt2@email.uky.edu Keywords: colorectal cancer; FASN; lipogenesis; patient-derived xenografts; TVB-3664 Received: March 27, 2018      Accepted: April 26, 2018      Published: May 15, 2018 ABSTRACT Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial. However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition. CRC cells and PDXs showed a wide range of sensitivity to FASN inhibition. TVB-3664 treatment showed significant response (reduced tumor volume) in 30% of cases. Anti-tumor effect of TVB-3664 was associated with a significant decrease in a pool of adenine nucleotides and alterations in lipid composition including a significant reduction in fatty acids and phospholipids and an increase in lactosylceramide and sphingomyelin in PDXs sensitive to FASN inhibition. Moreover, Akt, Erk1/2 and AMPK were major oncogenic pathways altered by TVBs. In summary, we demonstrated that novel TVB inhibitors show anti-tumor activity in CRC and this activity is associated with a decrease in activation of Akt and Erk1/2 oncogenic pathways and significant alteration of lipid composition of tumors. Further understanding of genetic and metabolic characteristics of tumors susceptible to FASN inhibition may enable patient selection and personalized medicine approaches in CRC.