Abstract A29: Evaluating the dynamics of epigenetic changes conferring targeted cancer drugs resistance in tumor xenograft propagation model

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancers. Although selective targeted therapy by kinase inhibitors have been emerged as important therapeutic agents in the treatment of a variety of human malignancies. Cancer cells become resistant to targeted cancer drugs are a major obstacle to successful cancer treatment. A major mechanism of resistance is the presence of a small sub-population of cancer cells have genetic changes, aberrant epigenetic modifications and activation of alternative signaling pathways by modifying the expression of several downstream effectors contribute to the acquisition of cancer target drug resistance. To dissect the alternate pathways exist to confer targeted cancer drugs resistance, the kinase inhibitors resistant cancer cells were established by continuous culture in increasing doses. Furthermore, the resistant cancer cells were inoculated into SCID mice and then tumors were excised and serially transplanted into additional mice for propagation. By in vivo serial dilution tumor-propagating assay, the established resistant cancer cell lines and xenografts were characterized using cell growth kinetics, targeted drug sensitivity and tumorigenicity. The gene overexpression and shRNA knockdown approaches were employed to investigate the mechanism of bypassing target gene effects from propagating cells in vitro. Confirmation of target drug sensitivity of drug resistant transfectants may allow for the identification of new therapeutic targets or prognostic biomarkers of cancer drugs response. The resistance-related genes having measurable effects in vitro and in vivo demonstrate that the established model in this study is appropriate for validation of genes that responsible for targeted drug resistance. Citation Format: REN-IN YOU, CHUN-SHAN CHEN, CHUN-YI CHEN, Simarmata Agustina. Evaluating the dynamics of epigenetic changes conferring targeted cancer drugs resistance in tumor xenograft propagation model. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A29.