FASN Inhibition as a Potential Treatment for Endocrine-Resistant Breast Cancer

Abstract

PurposeThe majority of breast cancers are estrogen receptor (ERα) positive making endocrine therapy a mainstay for these patients. Unfortunately, resistance to endocrine therapy is a common occurrence. Fatty acid synthase (FASN) is a key enzyme in lipid biosynthesis and its expression is commensurate with tumor grade and resistance to numerous therapies. MethodsThe effect of the FASN inhibitor TVB-3166 on ERα expression and cell growth was characterized in tamoxifen resistant cell lines, xenografts, and patient explants. Subcellular localization of ERα was assessed using a combination of immunofluorescence and subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by western blotting after treatment with TVB-3166 with or without the addition of palmitate or BAPTA. ResultsTVB-3166 treatment leads to a marked inhibition of proliferation in tamoxifen-resistant cells compared to the parental cells. Additionally, TVB-3166 significantly inhibited tamoxifen-resistant breast tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB-3166 treatment is mediated through the induction of endoplasmic reticulum stress. ConclusionOur preclinical data provide evidence that FASN inhibition by TVB-3166 presents a promising therapeutic strategy for treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine resistant breast cancer should be considered.

Fatty acid synthase as a new therapeutic target for HER2-positive gastric cancer

“…We tested the antitumor effects of TVB3166, a selective commercial FASN inhibitor [40], in OE19, N87, OE33 and GTR0455 gastrospheres.. TVB3166, tested at different concentrations, impaired in a dose-dependent manner the GFE (%) of GCSCs derived from the T-sensitive and T-resistant cell lines compared with vehicle (DMSO)-treated gastrospheres, with a statistical significance ranging from P < 0.05 to P < 0.005 (Fig. 4a).…”

Obesity and endocrine therapy resistance in breast cancer: Mechanistic insights and perspectives

“…Indeed, “in vitro” and “in vivo” treatment with a FASN inhibitor restored the sensitivity to the anti‐tumor activity of tamoxifen and fulvestrant 200 . Inhibition of FASN activity was also associated with a marked reduction of growth in tamoxifen‐resistant cell lines and tumor xenografts 202 …”

Protein palmitoylation in cancer: molecular functions and therapeutic potential

“…Two selective and potent FASN inhibitors, TVB‐3166 and TVB‐3664, were discovered and used in ovarian, lung, prostate and pancreatic cancer mouse models, which presented that inhibiting FASN in combination with taxane therapy inhibited tumor cell growth both in vitro and in vivo , possibly by disrupting tubulin palmitoylation, expression and microtubule organization [140]. Mechanistically, it is negotiable how exactly TVB‐3166 exerts its antitumor effect as another study showed that TVB‐3166 treatment alters ERα subcellular localization and reduces ERα levels by inducing endoplasmic reticulum stress, and exhibits antitumor activity in tamoxifen‐resistant breast tumor cells [141] (Table 1). Further investigations are warranted on this issue.…”