Abstract 5849: Valproic acid reverses trastuzumab resistance in erbB2-positive breast cancer cells via downregulation of ErbB2/ErbB3 signaling through induction of ErbB family members-targeting miRNAs

Amplification and/or overexpression of erbB2 occur in approximately 25% of invasive breast cancer and are significantly associated with a worse prognosis for breast cancer patients. Trastuzumab, a humanized monoclonal antibody against erbB2 receptor, has been successfully used in early-stage and metastatic breast cancer therapy of patients with erbB2-overexpressing tumors as monotherapy and in combination with other agents; however, both primary and acquired resistances to trastuzumab are common and currently represent a significant clinical problem. Thus, seeking of novel therapeutic strategies/agents to overcome trastuzumab resistance is vital to improve the survival of breast cancer patients whose tumors overexpress erbB2. In our current study, we explored whether valproic acid (VPA), a clinically used anticonvulsant drug with reported HDACi activity, reverses trastuzumab resistance in erbB2-positive breast cancer cells. We have found that VPA inhibits proliferation of both trastuzumab-sensitive SKBR3 and BT474 cell lines as well as their corresponding trastuzumab-resistant SKBR3-pool2 and BT474-HR20 cell lines in a dose- and time-dependent manner, which is accompanied by significant reduction of cyclin D1 as well as induction of P21. Meanwhile, VPA also induces caspase-dependent apoptosis in all aforementioned four cell lines. More interestingly, VPA not only significantly enhances the anti-proliferative effects of trastuzumab, but also potentiates trastuzumab-induced apoptosis in trastuzumab-sensitive and resistant cells. Our further mechanistic studies revealed that VPA treatment results in significant inactivation of PI3K/Akt signaling via simultaneous down-regulation of ErbB2 and ErbB3 in erbB2-positive breast cancer cancer cells, an effect which could be mainly arrtibuted to induction of ErbB family members-targeting microRNAs including miR-125a, miR-125b and miR-205 by VPA. Taken together, we presented here that VPA reverses trastuzumab resistance in erbB2-positive breast cance cells via downregulation of ErbB2/ErbB3 signaling in a miRNAs-inducing-dependent manner. Our data suggested that further investigation regarding the in vivo therapeutic effect of VAP against trastuzumab-resistant breast cancer should be of especial interest. Citation Format: Tingting Lin, Qun Ren, Weimin Zuo, Rong Lin, Hu Zhao, Ping Wang, Jianming Tan, Hui Lyu, Bolin Liu, Shuiliang Wang. Valproic acid reverses trastuzumab resistance in erbB2-positive breast cancer cells via downregulation of ErbB2/ErbB3 signaling through induction of ErbB family members-targeting miRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5849.