Abstract 7091: Significance of the tryptophan catabolism pathway in triple-negative breast cancer shows potential targets in certain subsets relating to the serine pathway

Abstract

Abstract Background: Breast cancer (BC) is the most prevalent form of cancer worldwide, encompassing 12.5% of all forms of cancers with the fifth highest mortality rate. Triple negative cancers (TNBC), which account for 15~20% of BCs, are one of the most aggressive and heterogeneous forms of BCs, characterized by the loss of ER, PR, and low HER2 expression. This heterogeneity and plasticity are partly due to the adaptable nature of their metabolism, a dynamic phenotype which is commonly observed in many aggressive forms of cancer. One of the key metabolic pathways that can confer this aggressive proliferative characteristic is the tryptophan catabolism pathway. Tryptophan is an essential amino acid required for the proper function of all mammalian cells, with IDO1 being a key enzyme that converts tryptophan to kynurenine, marking the start of the catabolism pathway. IDO1 expression is observed to be elevated in various types of cancer including BCs and has been associated with immune suppression/evasion via resource competition and tumor progression by supplying resources required for proliferation. Despite this, tryptophan catabolism is one of the lesser studied and understood pathways in cancer metabolism, especially in the context of TNBCs. Methods: Previous analysis had shown the tryptophan catabolism pathway is downregulated in certain subsets of TNBCs. To understand the effective function of the pathway with regards to proliferation, we targeted the upper-most step of the catabolism pathway by inhibiting IDO1 with epacadostat and indoximod in different types of TNBC cell-lines and observed for changes in their growth rates via proliferation assays. We also performed parallel stable-isotope tracer-based flux analysis with [U-13C11]-Tryptophan and [U-13C3]-Serine with mass spectrometry to characterize flux changes with the goal of discovering potentially lethal metabolic pathways. Results: We observed higher proliferative sensitivity to IDO1 inhibition in TNBC cell-lines with a genetic dysfunction in the de novo serine synthesis pathway. To understand these differences at the metabolic level, we quantified the differential contributions of tryptophan and serine to nucleotide and NAD+ synthesis and the TCA cycle with the parallel tracer experiments. Comparison of the lines with dysfunctional de novo serine synthesis to those with normal or amplified flux towards the pathway showed a higher interdependence with the kynurenine pathway in the dysfunctional group. These results indicate a differential potential for targeting the kynurenine pathway in relation with the serine synthesis pathway. Conclusion: Targeting the IDO1 enzyme in the kynurenine pathway shows significant correlations between the de novo serine pathway and the tryptophan catabolism pathway in TNBCs that may lead to metabolic targets conferring potential therapeutic benefits. Citation Format: Jin Heon Jeon, Abhinav Achreja, Mark Slayton, Olamide Animasahun, Minal Nenwani, Miya Paserba, Zackariah Farah, Sofia D. Merajver, Deepak Nagrath. Significance of the tryptophan catabolism pathway in triple-negative breast cancer shows potential targets in certain subsets relating to the serine pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7091.