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Preclinical evaluation of fatty acid synthase and egfrinhibition in triple-negative breast cancer

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

© Clinical Cancer Research, 2016, vol. 22, núm. 18, p. 4687-4697

American Association for Cancer Research

Autor: Giró Perafita, Ariadna
Palomeras, Sònia
Lum, David H.
Blancafort, Adriana
Viñas, Gemma
Oliveras, Glòria
Perez Bueno, Ferran
Sarrats Carbó, Ariadna
Welm, Alana L.
Puig i Miquel, Teresa
Data: 15 setembre 2016
Resum: 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
Format: application/pdf
Cita: 024171
ISSN: 1078-0432 (versió paper)
1557-3265 (versió electrònica)
Accés al document: http://hdl.handle.net/10256/12957
Llenguatge: eng
Editor: American Association for Cancer Research
Col·lecció: Versió postprint del document publicat a: http://dx.doi.org/10.1158/1078-0432.CCR-15-3133
Articles publicats (D-CM)
És part de: © Clinical Cancer Research, 2016, vol. 22, núm. 18, p. 4687-4697
Drets: Tots els drets reservats
Matèria: Mama -- Càncer
Breast -- Cancer
Càncer -- Tractament
Cancer -- Treatment
Inhibidors enzimàtics
Enzyme inhibitors
Títol: Preclinical evaluation of fatty acid synthase and egfrinhibition in triple-negative breast cancer
Tipus: info:eu-repo/semantics/article
Repositori: DUGiDocs

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