Mechanisms of Arginine Deprivation in Small Cell Lung Cancer

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Project Summary Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung tumor responsible for over 30,000 deaths each year in the US. SCLC has a two-year survival rate of ~6% with no approved targeted therapies beyond the recent approval of immunotherapy. SCLC is initially highly responsive to chemotherapy, but rapidly develops resistance leading to mortality in ~12 months. A major unmet need for SCLC treatment is the identification of new therapeutic targets and treatment strategies. SCLC has historically been treated as a single disease without patient stratification. SCLC is driven by distinct MYC family members (MYCL or MYC), which are notoriously difficult to drug. We and others showed that MYC and MYCL-driven SCLC have distinct molecular phenotypes with unique vulnerabilities to targeted therapies. We performed unbiased metabolite profiling on MYC versus MYCL-driven subtypes of SCLC and found that they are metabolically distinct. Using human cell lines, genetically-engineered mouse models (GEMMs), and human patient-derived xenografts (PDX), we found that MYC-driven SCLC is uniquely dependent on the amino acid arginine. Arginine depletion with pegylated arginine deiminase (ADI-PEG20) is the most effective drug we have tested in >25 drug combinations in GEMMs. Consistently, MYC-driven SCLC has reduced ASS1 expression, the enzyme required to synthesize arginine. In preliminary data, we discovered that MYC-driven tumor cells treated with ADI-PEG20 undergo autophagy and ferroptosis. After dramatic initial responses, tumors eventually relapse with re-expression of ASS1 and metabolic reprogramming with changes in one-carbon, polyamine, and ferroptosis-related pathways. We hypothesize that arginine deprivation in MYC-driven SCLC promotes autophagy and death by ferroptosis, and that inhibition of ferroptosis will improve the efficacy of ADI-PEG20. We also hypothesize that during ADI-PEG20 resistance, re- expression of ASS1 leads to metabolic reprogramming that can be blocked by targeting new metabolic pathways. To test these hypotheses, our objectives are: 1) Determine the function of autophagy and ferroptosis in response to arginine deprivation in SCLC. 2) Determine mechanisms of resistance to ADI-PEG20 and test new combination strategies to increase the efficacy of ADI-PEG20 treatment. This approach is innovative because we will employ our immune-competent GEMM of MYC-driven SCLC and new human PDX that recapitulate key features of the human disease. We will integrate state-of-the-art technologies in metabolite profiling and single cell RNA-seq to understand the mechanisms of resistance to arginine deprivation in vivo. This research is significant because arginine deprivation is being tested in numerous clinical trials in various cancer types and we are currently designing new clinical trials for ADI-PEG20 in SCLC. A better understanding of the functions of arginine deprivation may improve treatment of MYC-driven cancers and lead to more effective combination treatment strategies.