Abstract LB-311: Elevated kynureninase protein expression is associated with KEAP1 mutant non-small cell lung cancer and is predictive of poor overall survival

Abstract

Abstract Purpose: To identify signatures related to tryptophan metabolism independent of indoleamine 2,3-dioxygenase (IDO) that are predictive of tumor behavior. Introduction: Recent evidence has pointed to the importance of tryptophan catabolites on immune suppression and promotion of tumor growth. IDO1 is a rate-limiting enzyme in tryptophan catabolism currently targeted in clinical trials. Tryptophan catabolism can occur in IDO-negative tumors and resulting metabolites may have immunosuppressive and potential autocrine functions. Our late breaking finding is that we have uncovered signatures related to tryptophan metabolism independent of IDO that impact clinical outcome in NSCLC. Experimental Procedures: We initially carried out integrated genomic and proteomic profiling of 114 cancer cell lines. Small interfering RNA transfection experiments were used to evaluate the effect of KYNU knockdown on cell viability. TCGA data was analyzed to determine clinical relevance. Results: We identified kynureninase (KYNU), an enzyme involved in tryptophan metabolism that mediates formation of anthranilate and 3-hydroxyanthranilate, as uniquely overexpressed at the RNA and protein levels in NSCLC compared to other cancer types. These findings were not conserved for IDO or tryptophan 2,3-dioxygenase (TDO2), rate-limiting enzymes in tryptophan metabolism. Knockdown of KYNU reduced cell viability of NSCLC cell lines tested. Upregulation of KYNU was highly associated with KEAP1 mutational status and positively correlated with numerous Nrf-2 regulated-genes at both the protein and mRNA level. These findings were confirmed using TCGA data. KYNU mRNA levels predicted worse outcomes in stage II and III NSCLC adenocarcinoma and squamous cell carcinoma in TCGA cohorts independently of other covariates (P = : 0.008). Conclusion: We have uncovered a unique signature in NSCLC reflective of aberrant tryptophan metabolism mediated by elevated KYNU but not IDO/TDO2. KYNU expression is highly associated with KEAP1 mutational status. High KYNU mRNA levels was predictive of worse clinical outcomes in NSCLC. Citation Format: Johannes F. Fahrmann, Jennifer Dennison, Eunice Murage, Hong Wang, Edwin J. Ostrin, Ayumu Taguchi, Samir Hanash. Elevated kynureninase protein expression is associated with KEAP1 mutant non-small cell lung cancer and is predictive of poor overall survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-311.