Abstract 2050: Persistent STAT3 signaling contributes to the resistance of anti cancer drugs doxorubicin and cisplatin, and MEK inhibitor AZD6244 in human sarcoma cells

Abstract

Abstract Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway is activated in response to cytokines and growth factors. Persistently activated STAT3 are frequently detected in many types of human cancers and are believed to play an important role in their oncogenesis. Stat3 has been classified as a proto-oncogene because activated STAT3 can mediate oncogenic transformation in cultured cells and tumor formation in nude mice. We previously demonstrated that persistently activated STAT3 is frequently detected in human sarcoma such as rhabdomyosarcoma. To further examine the role of persistent TAT3 signaling plays in rhabdomyosarcoma, we used genetic approaches to either knock-down the expression of STAT3 using short hairpin RNA (ShRNA) or expressed constitutive active STAT3 protein. Knock-down the expression of STAT3 in rhabdomyosarcoma cells that express persistent STAT3 signaling, reduced the cell viability and sensitized cells to anti-cancer drugs doxorubicin and cisplatin. On the other hand, expression of constitutive active STAT3 protein in rhabdomyosarcoma cell lines lacking persistent STAT3 signaling decreased the sensitivity of those cells to doxorubicin and cisplatin. Furthermore, a MEK inhibitor, AZD6244 that is being tested in human cancer clinical trials unexpectedly induced STAT3 phosphorylation suggesting inducing of STAT3 may induce intrinsic resistance to MEK inhibitor. Accordingly, knock down of STAT3 sensitize sarcoma cells to MEK inhibitor treatments. To further translate our finding to potential cancer therapy, we tested a small molecular STAT3-selective inhibitor LY5 in sarcoma cells expressing persistent STAT3 signaling. Our data demonstrated that LY5 inhibited STAT3 phosphorylation, STAT3 DNA binding activity, and the migration of sarcoma cells. In addition, the combination of LY5 with anti-cancer drugs doxorubicin and cisplatin and the MEK inhibitor, AZD6244 also shown stronger inhibitory effects than single agent alone. In summary, our results using both genetic and small molecule approaches demonstrated that persistent STAT3 signaling contributes to the resistance of anti-cancer drugs doxorubicin and cisplatin, and MEK inhibitor in human sarcoma cells. They also implicated a potential cancer therapy strategy with the combination of STAT3 inhibitor with doxorubicin, cisplatin, and MEK inhibitor in sarcoma cells expressing persistent STAT3 signaling. Citation Format: Xiaojuan Wu, Hui Xiao, Chenglong Li, Jiayuh Lin. Persistent STAT3 signaling contributes to the resistance of anti cancer drugs doxorubicin and cisplatin, and MEK inhibitor AZD6244 in human sarcoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2050. doi:10.1158/1538-7445.AM2015-2050