Abstract 2026: Comprehensive metabolic flux analysis on triple-negative breast cancer shows potential collaterally lethal targets related to the serine pathway
Authors: Jeon Jin Heon , Achreja Abhinav , Slayton Mark , Animasahun Olamide , Paserba Miya , Roy Jyotirmoy , Nagrath Deepak , Merajver Sofia D. 
Published: June 2023

Background: Breast cancer (BC) is the most common cancer in the world with more than 2.26 million cancer cases in the year 2020 and causes the fifth-highest yearly deaths from cancer. Triple-Negative Breast Cancers (TNBC) comprise 15% of BC, are aggressive, highly heterogeneous, and have a lower 5-year survival than other subtypes. Cancer metabolism plays a major role on the heterogeneity and plasticity seen in tumorigenesis. Recent studies of cancer metabolism demonstrated that different metabolic pathways predominate in cancer cells that exhibit aggressive and metastatic behaviors, and adaptations in the tumor microenvironment also contribute to poor outcomes. Yet, metabolic mechanisms that influence tumorigenesis in TNBC remain poorly understood. Furthermore, the effect of widespread genetic alterations in TNBC are not well understood with regards to mechanisms of progression. Here we employ the Collateral Lethal Identification of Metabolic targets (CLIM) platform to uncover critical metabolic changes that confer survival in TNBCs with particular genomic alterations.

Methods: In TNBC, we sought models that exhibit with specific chromosomal amplifications that could influence serine biosynthesis, and in such models, we identified collateral lethal metabolic targets. In order to achieve insight into metabolic rewiring that occurs in TNBCs with chromosomal, we performed parallel stable-isotope tracer-based flux analysis on TNBC with or without the chromosomal amplifications of key regions. We used [U-13C6]-Glucose, [U-13C5]-Glutamine, [2H3]-Glucose, [2H4]-Glucose, [U-13C3]-Serine, and [U-13C11]-Tryptophan to establish and characterize the flux differences across the different TNBC cell-lines using mass spectrometry.

Results: With the parallel tracer experiments, we can accurately quantify the glycolytic pathway, pentose phosphate pathway, TCA cycle, de novo serine and nucleotide synthesis, and tryptophan catabolism. Our tracer-based flux analysis cumulatively indicates distinctions in fluxes through these pathways. Further, we observed that TNBC with dysfunctional de novo serine synthesis can be selectively targeted with collateral lethal metabolic pathways predicted by CLIM.

Conclusion: Comprehensive metabolic flux analyses show that a dysfunctional de novo serine synthesis pathway in TNBC with certain chromosomal or genomic alterations may offer relevant metabolic targets that can be tested for therapeutic benefits.

Citation Format: Jin Heon Jeon, Abhinav Achreja, Mark Slayton, Olamide Animasahun, Miya Paserba, Jyotirmoy Roy, Deepak Nagrath, Sofia D. Merajver. Comprehensive metabolic flux analysis on triple-negative breast cancer shows potential collaterally lethal targets related to the serine pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2026.