Abstract 2466: Stochastic loss of GLUL expression correlates with STK11-loss-dependent glutamine addiction and may impact anti-PD1 therapy resistance in NSCLC

Abstract

Abstract Our work aims to delineate the molecular interactions linking somatic disruption of Serine-Threonine Kinase 11 (STK11) with anti-PD1 therapy resistance in KRAS-driven lung adenocarcinoma (LUAD). Data presented here suggests glutamine synthetase (GLUL) may modulate this phenotype. Immune checkpoint inhibitors (ICIs), including anti-PD1 monoclonal antibody therapy, represent a promising therapeutic option for non-small cell lung cancer (NSCLC) patients. Unfortunately, efficient use of these drugs is hampered by an inability to accurately predict which patients will respond. Clinical observations have correlated anti-PD1 therapy resistance in KRAS-driven LUAD with somatic STK11 disruption, but the mechanism(s) responsible remains unknown. To investigate this connection we knocked out STK11 in three different human KRAS-driven LUAD cell lines and performed RNA-seq analysis to identify STK11-loss-dependent differentially expressed genes. Intriguingly, GLUL expression was reproducibly lost in a subset of KRAS-driven/STK11 null clones across two different human lung adenocarcinoma cell lines. GLUL is an enzyme that converts glutamate to glutamine. Glutamine is a critical metabolite supplying carbon and nitrogen necessary for amino acid, nucleotide, and lipid synthesis. Additionally, glutamine plays an important role in redox homeostasis, chromatin organization, and intra-tumoral signaling. Glutamine dependency is a common phenotype across many solid tumor types, and has previously been linked with STK11-deficiency in the context of polycystic kidney disease. Our current work suggests loss of GLUL expression correlates with an altered tumor-intrinsic response to nutrient stress in KRAS-driven LUAD culminating in immune evasion and anti-PD1 therapy resistance. Ongoing experiments aimed to define the relationship between STK11 loss and GLUL expression suggest this phenomenon is stochastic in nature and may provide tumor cells with a selective advantage. In conclusion, understanding the biology underlying the molecular connection between STK11 and GLUL may reveal reliable biomarkers for anti-PD1 therapy response and suggest a method for restoring sensitivity to current therapies. Citation Format: Sean M. Lenahan, Hailey M. Sarausky, David Joseph Seward. Stochastic loss of GLUL expression correlates with STK11-loss-dependent glutamine addiction and may impact anti-PD1 therapy resistance in NSCLC [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 2466.