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

Yekaterina Y Zaytseva,Hunter Moseley,Jennifer Harris,Timothy S Heuer,Anh-Thu Le,Timothy L Scott,Teresa Fan,Jinpeng Liu,Eun Y Lee,Chi Wang,Tianyan Gao,George Kemble,Robert M Flight,Ji Tae Kim,Piotr G Rychahou,Heidi L Weiss,Theru A Sivakumaran,Mark Evers,Andrew J Morris

doi:10.18632/oncotarget.25361

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.

Highlights

Colorectal cancer (CRC) is the 2nd most common cause of cancer death in the United States [1]
We evaluated the effect of TVB-3664 on tumor growth in nine colorectal cancer (CRC) patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to Fatty Acid Synthase (FASN) inhibition
The CRC cell lines exhibited a wide range of sensitivity to FASN inhibition, with low expression of FASN in SW480, SW620 and LIM2405 associated with resistance to FASN inhibition

Summary

Introduction

Colorectal cancer (CRC) is the 2nd most common cause of cancer death in the United States [1]. Despite advances in our understanding of the molecular basis of CRC and the increasing number of targeted therapies, treatment frequently remains disappointing, for advanced stages of disease [2, 3]. Activation of de novo lipogenesis in cancer cells, which is increasingly recognized as one of the characteristics of aggressive cancers [4], correlates with a poorer prognosis and shorter disease-free survival in many tumor types including CRC [5, 6]. Our published studies demonstrate an increase in expression of fatty acid synthase (FASN), a key enzyme of de novo lipogenesis, with advancing stages of CRC, suggesting an important role of de novo lipid synthesis in progression of this disease [6, 8]

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Conclusion