Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2(+) Breast Cancer.
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.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Yazan
Y
Alwarawrah
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Philip
P
Hughes
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
David
D
Loiselle
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
David A
DA
Carlson
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
David B
DB
Darr
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Jamie L
JL
Jordan
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Jessie
J
Xiong
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Lucas M
LM
Hunter
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Laura G
LG
Dubois
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
J Will
JW
Thompson
Departments of Microbial Infection and Immunity and Microbiology, Ohio State University, Room 788, BRT460 West 12th Avenue, Columbus, OH 43210, USA.
Manjusha M
MM
Kulkarni
Departments of Microbial Infection and Immunity and Microbiology, Ohio State University, Room 788, BRT460 West 12th Avenue, Columbus, OH 43210, USA.
Annette N
AN
Ratcliff
Departments of Microbial Infection and Immunity and Microbiology, Ohio State University, Room 788, BRT460 West 12th Avenue, Columbus, OH 43210, USA. Electronic address: jesse.kwiek@osumc.edu.
Jesse J
JJ
Kwiek
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: timothy.haystead@dm.duke.edu.
Timothy A J
TA
Haystead
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013552:Swine; D013876:Thiophenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054890:Fatty Acid Synthase, Type I; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013876:Thiophenes; C000624393:Fasnall compound; C518729:FASN protein, human; C508053:ERBB2 protein, human