In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 23_Supplement_1 ( 2022-12-01), p. IA014-IA014
Abstract:
Loss of adenomatous polyposis coli (APC) is considered a critical initiating event in colorectal cancer (CRC), where it occurs in 90% of sporadic CRCs. APC deficiency results in activation of WNT; however, major hurdles persist to therapeutic intervention of this pathway. Here, the synthetic essentiality framework was used to discover other potential druggable vulnerabilities for APC-deficient cancers. Through this approach, tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient CRC. Upregulation of TDO2 activates the Kyn-AhR pathway, increasing glycolysis. Subsequent cancer cell growth and CXCL5 secretion leads to macrophage recruitment into the tumor microenvironment. APC-deficient CRC models were found to be susceptible to both TDO2 depletion and pharmacologic inhibition. Overall, this study identifies the TCF4-TDO2-AhR-CXCL5 axis as a critical pathway in the maintenance of APC-deficient CRC, informing potential genotype-specific therapeutic targets and the use of TDO2 inhibitors to combat this disease. Citation Format: Rumi Lee, Jiexi Li, Jun Li, Chang-Jiun Wu, Shan Jiang, Wen-Hao Hsu, Deepavali Chakravarti, Peiwen Chen, Kyle A. LaBella, Jing Li, Denise J. Spring, Di Zhao, Y. Alan Wang, Ronald A. DePinho. Synthetic essentiality identifies TDO2 as a key target in APC-deficient CRC [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA014.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.CRC22-IA014
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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