FASN Inhibition and Taxane Treatment Combine to Enhance Anti-tumor Efficacy in Diverse Xenograft Tumor Models through Disruption of Tubulin Palmitoylation and Microtubule Organization and FASN Inhibition-Mediated Effects on Oncogenic Signaling and Gene Expression.
Palmitate, the enzymatic product of FASN, and palmitate-derived lipids support cell metabolism, membrane architecture, protein localization, and intracellular signaling. Tubulins are among many proteins that are modified post-translationally by acylation with palmitate. We show that FASN inhibition with TVB-3166 or TVB-3664 significantly reduces tubulin palmitoylation and mRNA expression. Disrupted microtubule organization in tumor cells is an additional consequence of FASN inhibition. FASN inhibition combined with taxane treatment enhances inhibition of in vitro tumor cell growth compared to treatment with either agent alone. In lung, ovarian, prostate, and pancreatic tumor xenograft studies, FASN inhibition and paclitaxel or docetaxel combine to inhibit xenograft tumor growth with significantly enhanced anti-tumor activity. Tumor regression was observed in 3 of 6 tumor xenograft models. FASN inhibition does not affect cellular taxane concentration in vitro. Our data suggest a mechanism of enhanced anti-tumor activity of the FASN and taxane drug combination that includes inhibition of tubulin palmitoylation and disruption of microtubule organization in tumor cells, as well as a sensitization of tumor cells to FASN inhibition-mediated effects that include gene expression changes and inhibition of β-catenin. Together, the results strongly support investigation of combined FASN inhibition and taxane treatment as a therapy for a variety of human cancers.
3-V Biosciences, Menlo Park, CA, USA. Electronic address: tim@celldesignlabs.com.
Timothy S
TS
Heuer
3-V Biosciences, Menlo Park, CA, USA.
Richard
R
Ventura
3-V Biosciences, Menlo Park, CA, USA.
Kasia
K
Mordec
3-V Biosciences, Menlo Park, CA, USA.
Julie
J
Lai
3-V Biosciences, Menlo Park, CA, USA.
Marina
M
Fridlib
3-V Biosciences, Menlo Park, CA, USA.
Douglas
D
Buckley
3-V Biosciences, Menlo Park, CA, USA.
George
G
Kemble
D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D054878:Lipoylation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C000615719:4-(1-(5-(3,4-dimethyl-1H-pyrazol-5-yl)-2,4-dimethylbenzoyl)azetidin-3-yl)benzonitrile; D000970:Antineoplastic Agents; D001384:Azetidines; D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; D009570:Nitriles; D011720:Pyrazoles; C000615721:TVB-3664; D043823:Taxoids; D014404:Tubulin; D051176:beta Catenin; C080625:taxane; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I
Docetaxel, combination; Fatty acid synthase; Inhibitor; Paclitaxel; Palmitoylation