MYC-driven small cell lung cancer is metabolically distinct and vulnerable to arginine depletion
| Autor: | Fang Huang, John S. Bomalaski, Guoying Wang, Marek Kudla, Milind D. Chalishazar, Younjee Lee, Matthew R. Guthrie, Sarah J. Wait, Nicholas T. Ingolia, Katarzyna Modzelewska, Kristofer C. Berrett, Sabina Cosulich, Abbie S. Ireland, Trudy G. Oliver, Jeffery M. Vahrenkamp, David H. Lum, Anandaroop Mukhopadhyay, Ralph J. DeBerardinis, Zeping Hu, Sophia S. Schuman, Jason Gertz |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms Arginine Transgene medicine.medical_treatment Mice Transgenic Disease Biology Models Biological Article Proto-Oncogene Proteins c-myc 03 medical and health sciences Mice 0302 clinical medicine Metabolomics Cell Line Tumor medicine Animals Humans neoplasms PI3K/AKT/mTOR pathway Chemotherapy TOR Serine-Threonine Kinases Small Cell Lung Carcinoma Xenograft Model Antitumor Assays humanities respiratory tract diseases Disease Models Animal 030104 developmental biology Oncology Cell culture 030220 oncology & carcinogenesis Cancer research Signal transduction Energy Metabolism Metabolic Networks and Pathways Signal Transduction |
| Popis: | 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 MYCL-driven subtypes of SCLC. Using genetic and pharmacologic approaches, we validated our findings in chemo-naïve 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 profiles. MYC-driven SCLC preferentially depends on arginine-regulated pathways including polyamine biosynthesis and mTOR pathway activation. Chemo-resistant SCLC cells exhibit increased MYC expression and similar metabolic liabilities as chemo-naïve 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. |
| Databáze: | OpenAIRE |
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