A wide range of cancers are either initially resistant to chemotherapy or are sensitive, but subsequently relapse through acquired drug resistance. Alterations in the p53 pathway are associated with drug resistance, underscoring its central role in determining response to chemotherapy. Using pediatric B-cell acute lymphoblastic leukemia as a model, we identified a set of p53-regulated transcriptional targets that comprise an apoptotic gene signature significantly associated with response to therapy and independently prognostic for outcome in pediatric ALL. We hypothesize that cells can be primed for an enhanced apoptotic response to chemotherapy by modulating expression levels of the p53-regulated apoptotic signature genes with small molecules before administering chemotherapy. We conducted a high-throughput screen to identify novel compounds that prime ALL cells for apoptosis to convert a chemotherapy-resistant cell into one that is sensitive. This screen was performed using 83,745 compounds in both the wild-type p53 cell line TK6 and the mutant-p53 line, WTK1. Cells were treated with either compound alone or compound plus daunorubicin, a drug used to treat ALL. Compounds were normalized and scored by using both the B-score and the robust Z-score. “Hits” were defined as compounds that do not significantly alter viability of the cells alone, but significantly increase daunorubicin-induced cell death. We confirmed the effects of the compounds in other B-cell ALL cell lines. In an effort in investigate mechanism, we looked at synergism using other chemotherapies with different modes of action. One compound was very synergistic with cisplatin, and we then extended the experiment to other cell types. We found that the synergism with cisplatin holds in all cell types tested, including T-cell ALL, lymphoma, breast, ovarian and colon cancer. In paired cisplatin-sensitive and resistant ovarian cancer cell lines, we find that the non-toxic doses of the compound can sensitize the resistant line and convert it to respond to cisplatin at the same doses as the parental sensitive line. Looking at the pathways induced by these compounds, we find important components in the cellular response to chemotherapy that can be manipulated to convert a chemoresistant cell into one that is sensitive.
Citation Format: Kathryn E. Wolak, Russell Bainer, Andrew Skol, Kenan Onel. Sensitizing cancer cells to chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3287. doi:10.1158/1538-7445.AM2013-3287