Abstract P6-11-02: Inhibition of mTOR and Fatty Acid Synthase (FASN) overcome acquired resistance to Trastuzumab, Lapatinib and both in HER2+ breast cancer

Abstract

Abstract Introduction: Resistance to dual biological blockade of HER2 positive breast cancer arises as a novel therapeutic challenge with high clinical relevance. We have shown that inhibition of fatty acid synthase (FASN) has anticancer activity and enhances the effect of chemotherapy and anti-HER2 drugs in pre-clinical breast cancer models. Furthermore, our group has recently observed that inhibition of FASN can reverse resistance to anti-HER2 therapies. The development of FASN inhibitors has consequently appeared as a novel anti-target modality for treating cancer. However, the clinical use of FASN inhibitors, such as Cerulenin, C75 and Epigallocatechin 3-gallate (EGCG) is limited by anorexia and induced body weight loss or by its low in vivo potency and stability. We synthesized novel EGCG-related inhibitors to improve their use as anti-tumor agents. Within these, G28UCM was selected for its inhibitory effect of FASN activity and selective cytotoxicity in tumor cells. Recently, it has been reported that mTOR blockade acts synergistically with HER2 inhibition to induce cell death and tumor regression in resistant breast cancer models. Materials and Methods: We have developed long term HER2+/ FASN+ breast cancer cell lines (SKBr3) resistant to the HER2-monoclonal antibody Trastuzumab (SKTR), the EGFR/HER2-tyrosine kinase inhibitor Lapatinib (SKLR) or both (SKLTR). Once established, we have characterized these cells by studying a panel of EGF receptors signaling proteins with western blot analysis, changes in adherence to extracellular matrix proteins and invasion capacity with colorimetric assays. Using MTT assay, we have assessed the effect of the mTOR-inhibitor, Temsirolimus, and G28UCM on viability of parental and resistant cells. The isobologram method has been used to estimate the possible synergistic effect between both treatments. Results: Resistant cells maintained downstream HER2 pathway activation by stimulating the expression/activation of alternative EGF family receptors and/or those specific ligands. Moreover, these cells increased adherence to extracellular matrix proteins and invasion capacity. Different combination regiment of Temsirolimus with G28UCM displayed a strong synergistic effect in inducing cell death of both, parental and resistant HER2+ breast cancer cells. Conclusions: The inhibition of mTOR and FASN is a potential novel therapeutic strategy in dual resistant HER2 positive breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-02.