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

Publication ,  Journal Article
Chalishazar, MD; Wait, SJ; Huang, F; Ireland, AS; Mukhopadhyay, A; Lee, Y; Schuman, SS; Guthrie, MR; Berrett, KC; Vahrenkamp, JM; Hu, Z ...
Published in: Clin Cancer Res
August 15, 2019

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

August 15, 2019

Volume

25

Issue

16

Start / End Page

5107 / 5121

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • TOR Serine-Threonine Kinases
  • Small Cell Lung Carcinoma
  • Signal Transduction
  • Proto-Oncogene Proteins c-myc
  • Oncology & Carcinogenesis
  • Models, Biological
  • Mice, Transgenic
  • Mice
  • Metabolic Networks and Pathways
 

Citation

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Chalishazar, M. D., Wait, S. J., Huang, F., Ireland, A. S., Mukhopadhyay, A., Lee, Y., … Oliver, T. G. (2019). MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion. Clin Cancer Res, 25(16), 5107–5121. https://doi.org/10.1158/1078-0432.CCR-18-4140
Chalishazar, Milind D., Sarah J. Wait, Fang Huang, Abbie S. Ireland, Anandaroop Mukhopadhyay, Younjee Lee, Sophia S. Schuman, et al. “MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion.Clin Cancer Res 25, no. 16 (August 15, 2019): 5107–21. https://doi.org/10.1158/1078-0432.CCR-18-4140.
Chalishazar MD, Wait SJ, Huang F, Ireland AS, Mukhopadhyay A, Lee Y, et al. MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion. Clin Cancer Res. 2019 Aug 15;25(16):5107–21.
Chalishazar, Milind D., et al. “MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion.Clin Cancer Res, vol. 25, no. 16, Aug. 2019, pp. 5107–21. Pubmed, doi:10.1158/1078-0432.CCR-18-4140.
Chalishazar MD, Wait SJ, Huang F, Ireland AS, Mukhopadhyay A, Lee Y, Schuman SS, Guthrie MR, Berrett KC, Vahrenkamp JM, Hu Z, Kudla M, Modzelewska K, Wang G, Ingolia NT, Gertz J, Lum DH, Cosulich SC, Bomalaski JS, DeBerardinis RJ, Oliver TG. MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion. Clin Cancer Res. 2019 Aug 15;25(16):5107–5121.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

August 15, 2019

Volume

25

Issue

16

Start / End Page

5107 / 5121

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • TOR Serine-Threonine Kinases
  • Small Cell Lung Carcinoma
  • Signal Transduction
  • Proto-Oncogene Proteins c-myc
  • Oncology & Carcinogenesis
  • Models, Biological
  • Mice, Transgenic
  • Mice
  • Metabolic Networks and Pathways