Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer
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Yekaterina Y. Zaytseva1, Piotr G. Rychahou2,3, Anh-Thu Le3, Timothy L. Scott4, Robert M. Flight4, Ji Tae Kim2, Jennifer Harris3, Jinpeng Liu2, Chi Wang2, Andrew J. Morris5, Theru A. Sivakumaran2, Teresa Fan4, Hunter Moseley4, Tianyan Gao2, Eun Y. Lee6, Heidi L. Weiss2, Timothy S. Heuer7, George Kemble7 and Mark Evers2,3
1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA
2Markey Cancer Center, University of Kentucky, Lexington, KY, USA
3Department of Surgery, University of Kentucky, Lexington, KY, USA
4RC-SIRM, University of Kentucky, Lexington, KY, USA
5Cardiovascular Research, University of Kentucky, Lexington, KY, USA
6Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA
73-V Biosciences, Menlo Park, CA, USA
Yekaterina Y. Zaytseva, email: email@example.com
Keywords: colorectal cancer; FASN; lipogenesis; patient-derived xenografts; TVB-3664
Received: March 27, 2018 Accepted: April 26, 2018 Published: May 15, 2018
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.
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