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


METHODS
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. Clin Cancer Res; 22(18); 4687-97. ©2016 AACR.
New Therapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain.
Ariadna
A
Giró-Perafita
New Therapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain.
Sònia
S
Palomeras
Oklahoma Medical Research Foundation, Program in Immunobiology and Cancer, Oklahoma City, Oklahoma.
David H
DH
Lum
New Therapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain.
Adriana
A
Blancafort
New Therapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain. Medical Oncology Department, Catalan Institute of Oncology (ICO) and Girona Biomedical Research Institute, Girona, Spain.
Gemma
G
Viñas
New Therapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain. Medical Oncology Department, Catalan Institute of Oncology (ICO) and Girona Biomedical Research Institute, Girona, Spain.
Glòria
G
Oliveras
New Therapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain. Pathology Department, Dr. Josep Trueta Hospital and Catalan Institute of Health (ICS), Girona, Spain.
Ferran
F
Pérez-Bueno
New Therapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain.
Ariadna
A
Sarrats
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Alana L
AL
Welm
New Therapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain. teresa.puig@udg.edu.
Teresa
T
Puig
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004317:Doxorubicin; D064429:Fatty Acid Synthases; D066246:ErbB Receptors; D000068818:Cetuximab