A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines

Puig, Teresa; Aguilar, Helena; Cufí, Sílvia; Oliveras, Glòria; Turrado, Carlos; Ortega Gutiérrez, Silvia; Benhamú, Bellinda; López-Rodríguez, María Luz; Urruticoechea, Ander; Colomer, Ramon

doi:10.1186/bcr3077

Cita bibliogràfica -- Enllaç permanent: https://ddd.uab.cat/record/113224

Web of Science: 70 cites, Scopus: 78 cites, Google Scholar: cites,

A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines
Puig, Teresa

(Institut d'Investigació Biomèdica de Girona)
Aguilar, Helena (Institut Català d'Oncologia)
Cufí, Sílvia (Institut d'Investigació Biomèdica de Girona)
Oliveras, Glòria (Institut d'Investigació Biomèdica de Girona)
Turrado, Carlos (Universidad Complutense de Madrid)
Ortega Gutiérrez, Silvia (Universidad Complutense de Madrid)
Benhamú, Bellinda (Universidad Complutense de Madrid)
López-Rodríguez, María Luz (Universidad Complutense de Madrid)
Urruticoechea, Ander (Institut Català d'Oncologia)
Colomer, Ramon

(Centro Oncológico MD Anderson (Madrid))

Data:	2011
Resum:	Introduction: Inhibiting the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of breast carcinoma cells, and this is linked to human epidermal growth factor receptor 2 (HER2) signaling pathways in models of simultaneous expression of FASN and HER2. Methods: In a xenograft model of breast carcinoma cells that are FASN+ and HER2+, we have characterised the anticancer activity and the toxicity profile of G28UCM, the lead compound of a novel family of synthetic FASN inhibitors. In vitro, we analysed the cellular and molecular interactions of combining G28UCM with anti-HER drugs. Finally, we tested the cytotoxic ability of G28UCM on breast cancer cells resistant to trastuzumab or lapatinib, that we developed in our laboratory. Results: In vivo, G28UCM reduced the size of 5 out of 14 established xenografts. In the responding tumours, we observed inhibition of FASN activity, cleavage of poly-ADPribose polymerase (PARP) and a decrease of p-HER2, p- protein kinase B (AKT) and p-ERK1/2, which were not observed in the nonresponding tumours. In the G28UCM-treated animals, no significant toxicities occurred, and weight loss was not observed. In vitro, G28UCM showed marked synergistic interactions with trastuzumab, lapatinib, erlotinib or gefitinib (but not with cetuximab), which correlated with increases in apoptosis and with decreases in the activation of HER2, extracellular signal-regulated kinase (ERK)1/2 and AKT. In trastuzumab-resistant and in lapatinib-resistant breast cancer cells, in which trastuzumab and lapatinib were not effective, G28UCM retained the anticancer activity observed in the parental cells. Conclusions: G28UCM inhibits fatty acid synthase (FASN) activity and the growth of breast carcinoma xenografts in vivo, and is active in cells with acquired resistance to anti-HER2 drugs, which make it a candidate for further pre-clinical development.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; Versió publicada
Publicat a:	Breast cancer research, Vol. 13, N. R131 (December 2011) , p. 1-13, ISSN 1465-542X