Abstract B14: TP53 synthetic lethal targets in colon cancer
| Autor: | Carlo M. Contreras, Charles C. Weige, Carolyn E. Banister, Phillip Buckhaults, Erin L. Anderson, Joseph H. Richardson, Changlong Liu |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Cancer Research. 77:B14-B14 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.crc16-b14 |
| Popis: | We have performed a genome-wide screen for pathways that are synthetic lethal with TP53 mutations in colon cancer. RKO colon cancer cells are wild type for TP53, and display robust p53-dependent growth arrest and apoptosis. We utilized an isogenic pair of RKO cells differing only in TP53 gene status (wild type vs homozygous null derivative) to screen a genome-wide GeCKO CRISPR library. After infection of these cells with the library and culturing for one week in vitro, we performed deep amplicon sequencing to identify CRISPR guide RNAs that were underrepresented in TP53 knockout cells. Multiple CRISPR guide RNAs targeting the CHEK1 and SHH genes were underrepresented in TP53 knockout cells. To validate these targets, we used CRISPR genome engineering to create an independent panel of six RKO clones with biallelic disruption of TP53, and tested small molecule inhibitors of CHEK1 (UCN01) and the SHH receptor SMO (Cyclopamine). TP53 null cells were tenfold more sensitive to UCN01, and 100-fold more sensitive to Cyclopamine, compared to TP53 wild type cells. Finally, the relevance of these findings to human colon cancers was confirmed by the establishment and treatment of colon cancer organoid avatars with either wild type or mutant TP53. Normal colon organoids, and tumor organoids with wild type TP53 were unaffected by either drug, whereas TP53 mutant organoids were significantly growth inhibited. Future studies will focus on testing these and additional targets, alone and in combination, against primary colon tumor and normal avatars and other preclinical models of TP53-mutant colon cancer. Citation Format: Charles C. Weige, Changlong Liu, Erin L. Anderson, Carolyn E. Banister, Joseph Richardson, Carlo Contreras, Phillip J. Buckhaults. TP53 synthetic lethal targets in colon cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B14. |
| Databáze: | OpenAIRE |
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