Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

Abstract

Purpose: Triple-negative breast cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of fatty acid synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC.Experimental Design: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG, or the combination in TNBC orthoxenograft models.Results: TNBC cell lines showed overexpression of FASN enzyme and its inhibition correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity.Conclusions: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC.

Anti‐Tumorigenic Potential of a Novel Orlistat‐AICAR Combination in Prostate Cancer Cells

“…FASN has moved from being a potential oncogenic marker to a definite chemotherapeutic target in several cancer types including breast and PCa [Giro-Perafita et al, 2016; Sadowski et al, 2014]. During this time it has become clear that cancer cells synthesize the vast majority of their fatty acids de novo , thereby relying on the cells energy machinery and lipogenic potential to increase their proliferation [Carvalho et al, 2008].…”

BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions

“…Thus, in addition to promoting CD24 internalization (this study), IRISOE by promoting EMT-inducers expression [36] could enhance breast cancer TICs formation. EGFR overexpression in the majority of TNBCs [5, 66], the close association between EGFR overexpression and activated p-c-Src Y416 membrane localization in TNBCs [67, 68], cortactin involvement in promoting stem-like phenotype as well as endocytosis in many cancers [30, 33, 34, 47, 69], and the fact that IRIS is overexpressed in 88% [38] EGFR is overexpressed in 75% [1, 70], vimentin is overexpressed in 88% [1, 6] and CD44 is overexpressed in 77% [71] of TNBCs, all support the internalization hypothesis as the major mechanism involved in IRISOE-induced CD24 cytoplasmic confinement in TNBC/TICs.…”

Metabolic Reprogramming in Triple-Negative Breast Cancer

“…Fatty acid synthase (FASN) has been found to be overexpressed in TNBC tumor cells (63). In preclinical models of TNBC tumors, FASN inhibitors in combination with anti-EGFR signaling agents show significant anti-tumor effects in TNBC tumors (64). Sterol regulatory element-binding protein (SREBP) is the master transcriptional regulator of lipogenic enzymes including ATP-citrate lyase, acetyl-CoA carboxylase, and FASN.…”