Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2(+) Breast Cancer

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2016 Jun 7

PMID 27265747

Citations 79

Authors

Yazan Alwarawrah

Philip Hughes

David Loiselle

David A Carlson

David B Darr

Jamie L Jordan

Jessie Xiong

Lucas M Hunter

Laura G Dubois

J Will Thompson

Manjusha M Kulkarni

Annette N Ratcliff

Jesse J Kwiek

Timothy A J Haystead

Affiliations

Soon will be listed here.

Abstract

Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2(+) breast cancer, particularly when combined with carboplatin.

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