Abstract 443: Synergistic inhibition of HER2 positive breast cancer by triptolide and lapatinib

Abstract

Abstract HER2-positive breast cancers are poorly differentiated and have a higher potential for metastasis. Although trastuzumab and lapatinib have been used for the treatment of HER2-positive breast cancer, resistance to both drugs has dampened the long-term benefit of those drugs. As cancer has multiple genetic aberrations and can readily develop resistance to individual drugs with specific targets, we employed synergistic drug combination as a strategy to overcome drug resistance and to enhance the efficacy of existing drugs. From a screen of the Johns Hopkins Drug Library, we identified triptolide as a strong synergistic hit with lapatinib in HCC1954, a drug-resistant HER2-positive breast cancer cell line. The combination of lapatinib and nontoxic doses of triptolide synergistically inhibited the HER2 signaling pathway. We found that lapatinib increased both mRNA expression and the half-life of HER2 protein, whereas triptolide countered the effects of lapatinib by downregulating the expression of HER2, leading to synergistic inhibition of the HER2 signaling pathway. The synergy in cell proliferation was observed in all HER2-positive breast cancer cell lines regardless of drug resistance status, but was absent in HER2-negative ones. In mouse xenograft models, the combination of lapatinib and triptolide at their minimum effective doses almost completely inhibited the growth of the drug-resistant HER2-positive breast cancer cells. Together, these findings suggest that the combination of triptolide and lapatinib could be a promising new therapeutic regimen for drug-resistant HER2-positive breast cancer. Citation Format: Paweena Chalugun, Joong Sup Shim, Preethi C. Korangath, Saraswati Sukumar, Jun O. Liu. Synergistic inhibition of HER2 positive breast cancer by triptolide and lapatinib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 443. doi:10.1158/1538-7445.AM2014-443