Abstract 1102: Integrated approach towards defining mechanism based combinations to guide clinical development of glutaminase inhibitors

Abstract Metabolic dysregulation is a hallmark of cancer, and recently, increasing evidence has shown a critical role for glutamine metabolism to support the bioenergetics and biosysnthetic needs of tumor and immune cells. We have previously disclosed the development of the GLS1 inhibitor, IPN60090, which is currently advancing through Phase 1 clinical studies (NCT03894540). Metabolic plasticity has been suggested to confer adaptive resistance to metabolic inhibitors and defines mechanisms that could be exploited to enhance therapeutic benefit. To address the clinical problems of innate drug resistance and adaptation, we interrogated metabolic and adaptive responses to IPN60090 in vitro and in vivo. We and others have previously identified KEAP1/NFE2L2 mutant non-small cell lung cancer models as sensitive to GLS1 inhibition. Through an integrated approach, including metabolic, transcriptomic, and proteomic analysis, we have identified molecular pathways that confer resistance to GLS1 inhibition. Nodes in these pathways that drive aquired resistance, may serve as additional patient stratification biomarkers in subsets on NSCLC or provide opportunites for further drug development. Additionally, unbiased in vivo functional genomics screening identified mulitple signaling pathways that act as critical nodes governing resistance to GLS1 inhibition. Drug combinations were tested in vitro and in vivo to identify those that are most synergistic with IPN60090. We found that PI3K/AKT/mTOR signaling is a major contributor to IPN60090 resistance, and we demonstrate that dual targeting of GLS1 and PI3K/AKT/mTOR signaling in tumors with KEAP1/NFE2L2 mutations results in synergistic anti-tumor efficacy. IPN60090, dosed in combination with inhibitors of these pathways yields regressions and off-treatment, durable responses in preclinical models of KEAP1-mutant NSCLC. Based on these data, combination strategies are being developed for Phase 1b expansion cohorts. Citation Format: Jeffrey J. Kovacs, Nakia D. Spencer, Christopher A. Bristow, Alessandro Carugo, Virginia Giluiani, Meredith A. Miller, Angela Harris, Ningping Feng, Michael L. Soth, Kang Le, Elisa de Stanchina, Charles M. Rudin, Giulio Draetta, Timothy A. Yap, Philip Jones, Timothy Heffernan. Integrated approach towards defining mechanism based combinations to guide clinical development of glutaminase inhibitors [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 1102.