Abstract A39: Repurposing of AP-102 and AP-103 in the treatment of breast cancer via inhibiting the RAF/ERK pathway

Breast cancer is a serious health care issue with millions of women being diagnosed worldwide. Although RAS is mutated in only a minor fraction of breast cancers, the Ras signaling pathway is hyperactivated in half of these tumors. Tamoxifen is most commonly used as hormone therapy for breast cancer, which usually accompanied not serious but bothersome side effects. AP-102 and AP-103 are approved drugs in treating diabetes and antipyretic and analgesic, respectively. Repurposing approved drugs for cancer represents an opportunity to improve advance patients therapies based on the new findings and clinical treatment experience via new proposed signaling pathway. In this study, the antitumor efficacy of two drugs was evaluated on the estrogen-dependent ZR-75-1 human breast cancer xenograft model. The tumor-bearing mice were randomly divided into 5 groups and administrated with vehicle, AP-102, AP-103, AP-102 plus AP-103, and paclitaxel, respectively. Results showed that the tumor inhibition rate of AP-102, AP-103, AP-102/AP-103, and paclitaxel were 27.25%, 17.3%, 43.42%, and 14.25%, respectively. Mechanistic analyses revealed that combination of AP-102 and AP-103 is deduced by inhibiting RAF/ERK activation. Moreover, the mice treated with AP-102/AP-103 showed an increase of 36.5% in white blood cell count compared with the mice treated with vehicle. These data posed an apparent anticancer effect in combination of AP-102 and AP-103 with significant difference, which might be associated with innate immunity evidenced by increased WBC number. For in vitro cytotoxicity, ZR-75-1 cells showed more resistant to paclitaxel than MDA-MB-231 cells. This study provides the important information that combination of two drugs, AP-102 and AP-103, might have potential therapeutic use for tumor cells with highly expressed estrogen receptors or breast tumor resistance to chemo drugs. Citation Format: Pei-Yi Tsai, Yu-Sian Ding, Le-Mei Hung, Yueh-Feng Ho, Ling-Chiu Peng, Chiung-Wen Liou, Jia-Ming Chang. Repurposing of AP-102 and AP-103 in the treatment of breast cancer via inhibiting the RAF/ERK pathway. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A39. doi: 10.1158/1557-3125.RASONC14-A39