In Vivo and In Vitro Evidence of Antitumor Activity of UCM-Gi028 [Novel FASN Inhibitor] Against Trastuzumab-Resistant Breast Cancer.

Abstract

Abstract Introduction. 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 previously shown that inhibition of Fatty Acid Synthase (FASN) activity, an enzyme overexpressed and hiperactivated in breast carcinoma leads to apoptosis in breast cancer cells and its effect is tightly linked to Her-2 signalling pathways. Here we show the anticancer effect of UCM-Gi028, the lead-compound of the first generation of a novel family of synthetic FASN inhibitors, both in vitro and in an animal model of Her-2 amplified breast cancer.Material and Methods. We analysed the cellular and molecular effects of UCM-Gi028 alone or in combination with lapatinib, erlotinib, trastuzumab and gefitinib in a Her-2 dependent breast cancer cell line (AU565) using epigallocatechin-3-gallate (EGCG), a natural inhibitor of FASN, as a comparator. We also generated a long-term trastuzumab resistant pool from AU565 cells (AU565TTZR pool) to evaluate the effect of UCM-Gi028 in this setting. We further characterize the toxicity profile, anti-cancer activity and pharmacodynamic markers in an athymic mice model of Her-2 positive breast cancer cell line xenograft tumors.Results. UCM-Gi028 shows marked synergic antitumoral activity combined with lapatinib, erlotinib, trastuzumab and gefitinib (p <0.05). Response to co-exposure of UCM-Gi028 plus growth-signal inhibitors was significantly correlated with induction of apoptosis and with decrease in the activation forms of HER-2, MAPK and AKT, as markers of drug activity. Importantly, AU565TTZR pool displayed increased sensitivity to UCM-Gi028 compared to previously known FASN inhibitors (EGCG and C75). In the Her-2 positive breast cancer animal model study no weight loss or other relevant toxicity were observed after long term (7 weeks) exposure to UCM-Gi-28. A group of UCM-Gi028-treated mice showed tumour regression compared to control and, importantly, responsive tumours showed inhibition of FASN activity, increased apoptosis and decreased HER-2, AKT and MAPK activity.Discussion. As compared to its related natural compound (EGCG), UCM-Gi-28 shows increased antitumor activity with a favourable toxicity profile, in contrast with other, highly toxic, synthetic FASN inhibitor (C75). UCM-Gi028 antitumour activity remains unchanged in trastuzumab resistant cells. UCM-Gi-28 warrants further pre-clinical and clinical development alone or in combination with other anticancer agents in Her-2 positive breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5079.