The vast majority of Her-2 positive advanced breast cancer patients develop resistance to trastuzumab based therapies within the first year of treatment. We have shown that inhibition of Fatty Acid Synthase (FASN) activity, an enzyme overexpressed and hiperactivated in breast carcinoma, shows marked synergic anticancer activity combined with anti-HER drugs. To examine the molecular mechanisms of acquired resistance to HER2, we have generated clones of FASN+ and HER2+ cell lines (AU565 and SK-Br3) resistant to trastuzumab (TTZ) and lapatinib (LAP) for longer than 9 months, and have evaluated the anticancer effect of UCMG028. We further characterized the effect of UCM028 in a mice model of HER2+ xenograft (BT474). TTZ and LAP-resistant cells displayed an increased sensitivity to UCMG028 compared to previously known FASN inhibitors (C75 and EGCG). Gene expression profiling of LAP and TTZ-resistant cells showed a significant differential expression in different sets of genes involved on cell cycle pathways. Mice BT474 xenografts showed tumor regression after long-term exposure to UCMG028. Preliminary toxicity data showed no weight loss, and histological studies (H&E, Masson's Tricromic, Sudan Black B and Picrosirius Red Stains) showed no structural myocardial abnormalities in treated mice with UCMG028-treated mice. Thus, UCMG028 is an effective anticancer treatment for HER2 + breast cancer and its activity remains unchanged in TTZ and LAP resistant cells. Taken together, these data suggest that FASN activity inhibition by UCMG028 could be a new therapeutic strategy in HER2 + breast cancer with potential to overcome resistance to standard anti-HER2 therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3573.