Abstract 1112: Exploiting oncogene-conferred glutamine addiction as a therapeutic vulnerability in resistant mantle cell lymphoma

Abstract

Abstract Mantle cell lymphoma (MCL) is an incurable B cell non-Hodgkin's lymphoma characterized by high refractory occurrence following drug treatment, and the novel therapeutic strategies targeting resistant mechanisms are crucial. Our group has recently shown that among the highly proliferative MCL population, a subpopulation of ibrutinib resistant (IBN-R) cells exhibits increased OXPHOS activity that is fueled by increased glutaminolysis and rely more on mitochondrial respiration for their growth and survival. Recently, glutamine has been proposed to be the essential amino acid in the malignant metabolism, confers those specific tumors with glutamine addiction. Accordingly, such addiction is interplayed with several oncogenic pathways including Myc and mTOR. Our previous studies indicate the increased Myc copies in IBN-R MCL. Therefore, our aim of this work was to uncover the relationship between glutamine addiction with MCL resistance. In the work presented, we focused on glutaminase (GLS), the enzyme that converts glutamine to glutamate, a precursor of α-ketoglutarate that links glutamate to the TCA cycle. Incorporation of α-KG into the TCA cycle is a major anaplerotic step in proliferating cells and is critical for the maintenance of TCA cycle function. Targeting glutamine addiction and glutamine-fueled OXPHOS would act as a potential therapeutic strategy in conquering drug resistance in glutamine-addicted MCL. We presented evidence that GLS1 is highly increased in IBN-R and CART-R MCL patient samples by immunoblotting. To identify a clinical actionable GLS inhibitor for the treatment of MCL, we chose a GLS1 specific inhibitor CB-839 (Selleckchem), currently under several phase II and III clinical trials investigations on solid tumors. Inhibiting GLS1 with CB-839 decreases the cell viability in MCL (IC50=0.56nM-308.4nM). Of note, the combinatory treatment of GLS and OXPHOS inhibitor, IACS-010759, induces apoptosis (53% compared with control, and 33%-50% with single agent). Furthermore, the combinatory treatment also shows synergistic effects in decreasing cell viability in IBN-R MCL cell line, Z-138 (CI=0.44), as well as in decreasing mitochondrial membrane potential (≈16% compared with single agent, and 32% with control) and increasing ROS generation (6 times to control, and 3-4 times to single agent). Importantly, while CB-839 is continuing its validation in several solid tumor models, this is the first study providing data on its efficacy in preclinical models of MCL. In conclusion, we report that glutaminolysis and OXPHOS are upregulated in IBN-R MCL that could be partially due to high expression of GLS1. Our preliminary results revealed that the GLS inhibitor, CB-839, may present a clinical potential for a new indication and the combinatory treatment with our in-house inhibitor, IACS-010759, warrants more in-depth investigation as a novel therapeutic regimen. Citation Format: Lingzhi Li, Changying Jiang, Lucy J. Navsaria, Yang Liu, Joseph M. McIntosh, Michael Wang, Yinxin Yao. Exploiting oncogene-conferred glutamine addiction as a therapeutic vulnerability in resistant mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1112.