MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion

Abstract

Purpose: Small-cell lung cancer (SCLC) has been treated clinically as a homogeneous disease, but recent discoveries suggest that SCLC is heterogeneous. Whether metabolic differences exist among SCLC subtypes is largely unexplored. In this study, we aimed to determine whether metabolic vulnerabilities exist between SCLC subtypes that can be therapeutically exploited.Experimental Design: We performed steady state metabolomics on tumors isolated from distinct genetically engineered mouse models (GEMM) representing the MYC-and MYCLdriven subtypes of SCLC. Using genetic and pharmacologic approaches, we validated our findings in chemo-na€ ve and -resistant human SCLC cell lines, multiple GEMMs, four human cell line xenografts, and four newly derived PDX models.Results: We discover that SCLC subtypes driven by different MYC family members have distinct metabolic pro-files. MYC-driven SCLC preferentially depends on arginineregulated pathways including polyamine biosynthesis and mTOR pathway activation. Chemo-resistant SCLC cells exhibit increased MYC expression and similar metabolic liabilities as chemo-na€ ve MYC-driven cells. Arginine depletion with pegylated arginine deiminase (ADI-PEG 20) dramatically suppresses tumor growth and promotes survival of mice specifically with MYC-driven tumors, including in GEMMs, human cell line xenografts, and a patient-derived xenograft from a relapsed patient. Finally, ADI-PEG 20 is significantly more effective than the standard-of-care chemotherapy.Conclusions: These data identify metabolic heterogeneity within SCLC and suggest arginine deprivation as a subtype-specific therapeutic vulnerability for MYC-driven SCLC. DiscussionDespite numerous clinical trials and years of research, therapeutic options for SCLC remain limited. However, recent studies suggest that molecular subtypes of SCLC exist with distinct

AKT but not MYC promotes reactive oxygen species-mediated cell death in oxidative culture

“…Increased glycolytic activity is thought to help satisfy the rapacious demands of highly proliferative cancer cells for biosynthetic precursors including lipids, proteins and nucleic acids. However, this altered metabolism can leave tumors vulnerable to metabolic disruptions such as starvation of substrates including glucose, asparagine, glutamine, methionine, serine and others (Chalishazar et al, 2019;Gao et al, 2019;Graham et al, 2012;Joly et al, 2020;Maddocks et al, 2013;Wise et al, 2008;Yuneva et al, 2007). Therefore, understanding the interplay between oncogenes and metabolism is essential to understand how to design therapeutic strategies targeting tumor metabolism (Galluzzi et al, 2013;Martinez-Outschoorn et al, 2017).…”

Leveraging insights into cancer metabolism—a symposium report

“…In addition, chemotherapy‐resistant cells are more likely to have high levels of C‐MYC and are more sensitive to arginine depletion. In mouse models of SCLC, depleting arginine had no effect on survival in mice with L‐MYC–driven tumors, but was significantly better than chemotherapy in improving the survival in mice with C‐MYC–driven tumors …”

“…Steady‐state metabolomic profiling in collaboration with Ralph DeBerardinis's laboratory has shown that C‐MYC–driven tumors are metabolically distinct from L‐MYC–driven tumors . C‐MYC–driven tumors show an enrichment in nucleotide biosynthesis and arginine metabolism .…”

“…16,17 C-MYC-driven tumors show an enrichment in nucleotide biosynthesis and arginine metabolism. 16 Oliver's work has focused on understanding the effect of arginine metabolism, while DeBerardinis presented their work on understanding the effect of increased nucleotide biosynthesis later in the symposium.…”

“…In mouse models of SCLC, depleting arginine had no effect on survival in mice with L-MYC-driven tumors, but was significantly better than chemotherapy in improving the survival in mice with C-MYC-driven tumors. 16 Oliver's data show that C-MYC-driven SCLC has unique metabolic vulnerabilities and is highly dependent on arginine for survival. Drugs that deplete arginine may be effective for a disease that has eluded both targeted and immunotherapies to date.…”