Investigating and targeting metabolic vulnerabilities of MYC-driven small cell lung cancer

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PROJECT ABSTRACT Small cell lung cancer (SCLC) is a fatal neuroendocrine lung tumor that is challenging to treat due to early metastasis, rapid growth, and a lack of easily targetable driver alterations. For the last ~40 years, SCLC has been treated primarily as a single disease in the clinic with combination, platinum-based chemotherapy that offers a median survival of only ~10-12 months. It is imperative to better understand SCLC biology to enable development of novel treatment strategies that effectively prolong patient survival. SCLC tumors amplify or overexpress one oncogenic MYC family member: MYC, MYCL, or MYCN. MYC-high SCLCs are metabolically distinct from MYC-low, and have specific and targetable metabolic vulnerabilities. The most effective therapeutic strategy for treatment of MYC-high SCLCs in preclinical trials is deprivation of circulating arginine by pegylated arginine deiminase (ADI-PEG20). MYC-high SCLCs are particularly sensitive to ADI-PEG20, because they lack the enzyme argininosuccinate synthetase 1 (ASS1) that catalyzes de novo synthesis of arginine by the urea cycle. Still, SCLC tumors eventually develop resistance to ADI-PEG20 (ADIR) that corresponds with re- expression of ASS1. Upon ADIR, tumors acquire secondary metabolic dependencies that may be targeted to prolong ADI-PEG20 response and patient survival. Preliminary data show that ADIR SCLC depends on serine and one-carbon (1C) metabolism, which can be targeted with anti-folates. Preliminary data also delineate candidate transcriptional regulators that may govern ADIR in SCLC. Activating transcription factor 4 (ATF4), a stress-responsive transcription factor, is one predicted upstream regulator of gene programs enriched in ADIR vs naïve SCLCs—determined by bulk and single-cell RNA sequencing. ATF4 is induced upon acute arginine deprivation in SCLC and continues to be expressed with its target genes during ADIR. Here, the applicant will employ a single-cell RNA-seq-derived model of SCLC response to ADI-PEG20, metabolite profiling, in vivo isotope tracing, and CRISPR-based gene editing to interrogate whether ATF4 governs ADIR. The hypothesis for this research is that ATF4 drives ADIR by enhancing serine and 1C metabolism in an ASS1-dependent manner. Experiments will be performed in two specific aims to test whether ATF4 governs: 1) the sensitivity of MYC-high SCLCs to ADI-PEG20, and/or 2) the sensitivity of ADIR SCLCs to 1C metabolism inhibitors. Knowledge gleaned from this research will inform combination treatment strategies that improve the efficacy of ADI-PEG20 and extend survival of patients with SCLC and other ASS1-low tumors. The proposed research will provide unique opportunities for the applicant to gain expertise in cancer biology, cancer metabolism, and computational analysis of -omics data—three major goals of the applicant’s training plan. The proposed research will occur over three years of training at Huntsman Cancer Institute and the University of Utah, a collaborative and resource-rich training environment, in the lab of Dr. Trudy Oliver.