Abstract 4828: Newly identified p53 pathway-restoring compound CB002 and its derivatives sensitize colorectal and multiple myeloma cancer cell lines to front-line cancer therapies

Abstract

Abstract Proapoptotic NOXA protein is a p53 transcriptional target that has been shown to be a crucial mediator of cell death in response to chemotherapy agents. Given the fact that NOXA is downregulated in multiple cancers, induction of this protein by small-molecule exposure makes it an attractive therapeutic strategy. Although cancer patients often respond to initial therapy, later on therapy resistance develops, leaving them with limited therapy options. Therefore, new therapeutic regimens that overcome resistance mechanisms are of high importance. The purpose of this study was to identify new small molecules that restore the p53 pathway and, in combination with chemotherapy agents, could result in therapy sensitization. We have discovered a family of small molecules (CB002 and 12 structural analogs) that restore the p53 pathway through NOXA in various cancer cell lines including SW480, DLD-1 and HCT116 colorectal cancer (CRC) cells. In order to test if CB002 and its derivatives sensitize cells to first-line CRC therapies, we treated SW480 and DLD-1 cells in combination with irinotecan, fluorouracil (5-FU), doxorubicin, or oxaliplatin. Our data suggest that treatment combinations of CB002 with first-line CRC therapies result in enhanced cell death and decreased IC50. Particularly, sensitization to doxorubicin and irinotecan was dependent on NOXA expression as stable NOXA knockdown abolished therapy sensitization. NOXA induction has been shown to overcome bortezomib resistance in multiple myeloma (MM) cells. Thus, we investigated if CB002 and more potent derivatives could resensitize bortezomib-resistant cells. We treated MM1S (bortezomib-sensitive) and 33X (bortezomib-resistant) cells with bortezomib along with our CB002 structural analogs. Our data indicate that combination treatment with our structural analogs sensitizes 33X cells to bortezomib treatment. Taken together, our evidence supports that our novel identified structural analogs of CB002 can be further tested in vivo in combination with front-line therapies to improve therapeutic modalities and overcome resistance in CRC and MM. Our experiments will further assess toxicity to normal cells and tissues. Current experiments are focused on using NOXA as a pharmacodynamic biomarker to predict therapeutic efficacy. Our data argue that p53 pathway restoring compounds are worth pursuing further to determine if they can provide a therapeutic advantage to patients who are not responsive to front-line cancer therapies. Citation Format: Liz J. Hernandez Borrero, David T. Dicker, Wafik S. El-Deiry. Newly identified p53 pathway-restoring compound CB002 and its derivatives sensitize colorectal and multiple myeloma cancer cell lines to front-line cancer therapies [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 4828.