Synthetic Essentiality of Tryptophan 2,3-dioxygenase 2 in APC-Mutated Colorectal Cancer

Inactivation of the adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers (CRC). APC-deficiency activates WNT signaling which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient CRC. Mechanistically, APC-deficiency results in TCF4/ B-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit macrophages into the tumor microenvironment. Therapeutically, APC-deficient CRC models were susceptible to TDO2 depletion or pharmacological inhibition which impaired cancer cell proliferation and enhanced anti-tumor immune profiles. Thus, APC-deficiency activates a TCF4-TDO2-AhR-CXCL5 circuit that impacts multiple cancer hallmarks via autonomous and non-autonomous mechanisms and illuminates a genotype-specific vulnerability in CRC.