Broad Glutamine Pathway Inhibition by DRP-104 Results in Anti-Tumor Activity in Hypermetabolic Lung Tumors Resistant to PD-1 or Osimertinib Therapy.

Abstract Recent breakthroughs with checkpoint inhibitors (CPI) or the third generation tyrosine kinase inhibitor (TKI) osimertinib (OSI) for patients with specific mutations to the epidermal growth factor receptor (EGFR) gene are now able to induce durable responses in non-small cell lung cancer (NSCLC) patients1,2. However, the majority of patients who receive CPI or OSI will be either non-responsive to treatment or develop therapy resistance. We sought to identify alternative treatment strategies to overcome therapy resistance by targeting metabolism in aggressive tumors. The fast rate of growth in therapy resistant hyper-metabolic tumors (HMTs) makes them dependent on nutrients to sustain anabolic growth. To demonstrate this dependency, we coupled PET imaging using 18F-FDG and 11C-Glutamine (11C-GLN) with in vivo metabolomics and identified a conserved metabolic signature in which lung squamous cell carcinomas (LUSC) and EGFR mutant lung adenocarcinomas (LUAD) were marked by dependence upon both glucose and glutamine3,4. Importantly, this metabolic signature is predictive of either response or resistance to targeted therapies that inhibit glucose and glutamine metabolism that may be exploited in a clinical setting.We previously reported that combined targeting of glucose and glutamine metabolism with mTOR kinase inhibitor TAK228 or TKI in combination with the selective glutaminase (GLS) inhibitor CB-839 was required to significantly suppress glucose and glutamine metabolism in both LUSC and EGFR mutant LUADs resulting in metabolic crisis and tumor cell death3,5. Here, we tested the novel broad acting glutamine antagonist, DRP-104, as a single agent or in combination with anti-PD-1 in CPI-resistant LUSC and in EGFR mutant LUAD tumor models. DRP-104 significantly inhibited tumor progression across genetically engineered mouse models (GEMMs) with biallelic deletion of lkb1, pten and p53 (Lkb1-/-;Pten-/-;P53-/-) and patient derived xenograft (PDX) models of LUSC. Importantly, LUSC showed significant single agent response to DRP-104 and the combination of DRP-104 and anti-PD-1 treatment demonstrated therapeutic synergy, suggesting that broad inhibition of glutamine metabolism by DRP-104 induced metabolic remodeling of the tumor immune microenvironment and permissiveness to CPI blockade6. Likewise, we showed that DRP-104 induced a significant response in an OSI-resistant PDX model of EGFR mutant LUAD. Overall, DRP-104 showed great potential to treat hypermetabolic therapy-resistant LUSC and EGFR mutant LUAD as a single-agent therapy and in combination with immune CPI. Further clinical development of DRP-104 in this patient population is warranted and clinical trials are currently ongoing. Citation Format: Morgan Brady, Milica Momcilovic, Chiara Montemurro, Yumi Yokoyama, Heather Christofk, Katerina Politi, Margaret Dugan, Aaron Lisberg, Robert Wild, David B. Shackelford. Broad glutamine pathway inhibition by DRP-104 results in anti-tumor activity in hypermetabolic lung tumors resistant to PD-1 or osimertinib therapy [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 1572.