MYC-driven small-cell lung cancer is metabolically distinct and vulnerable to arginine depletion

Milind D. Chalishazar, Sarah J. Wait, Fang Huang, Abbie S. Ireland, Anandaroop Mukhopadhyay, Younjee Lee, Sophia S. Schuman, Matthew R. Guthrie, Kristofer C. Berrett, Jeffery M. Vahrenkamp, Zeping Hu, Marek Kudla, Katarzyna Modzelewska, Guoying Wang, Nicholas T. Ingolia, Jason Gertz, David H. Lum, Sabina C. Cosulich, John S. Bomalaski, Ralph J DeBerardinisTrudy G. Oliver

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 MYCL-driven 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 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-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.

Original languageEnglish (US)
Pages (from-to)5107-5121
Number of pages15
JournalClinical Cancer Research
Volume25
Issue number16
DOIs
StatePublished - Aug 15 2019

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Small Cell Lung Carcinoma
Arginine
Heterografts
Cell Line
Neoplasms
Metabolomics
Metabolome
Polyamines
Standard of Care
Research Design
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. Clinical Cancer Research, 25(16), 5107-5121. https://doi.org/10.1158/1078-0432.CCR-18-4140

MYC-driven small-cell lung cancer is metabolically distinct and vulnerable to arginine depletion. / Chalishazar, Milind D.; Wait, Sarah J.; Huang, Fang; Ireland, Abbie S.; Mukhopadhyay, Anandaroop; Lee, Younjee; Schuman, Sophia S.; Guthrie, Matthew R.; Berrett, Kristofer C.; Vahrenkamp, Jeffery M.; Hu, Zeping; Kudla, Marek; Modzelewska, Katarzyna; Wang, Guoying; Ingolia, Nicholas T.; Gertz, Jason; Lum, David H.; Cosulich, Sabina C.; Bomalaski, John S.; DeBerardinis, Ralph J; Oliver, Trudy G.

In: Clinical Cancer Research, Vol. 25, No. 16, 15.08.2019, p. 5107-5121.

Research output: Contribution to journalArticle

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 2019, 'MYC-driven small-cell lung cancer is metabolically distinct and vulnerable to arginine depletion', Clinical Cancer Research, vol. 25, no. 16, pp. 5107-5121. https://doi.org/10.1158/1078-0432.CCR-18-4140
Chalishazar, Milind D. ; Wait, Sarah J. ; Huang, Fang ; Ireland, Abbie S. ; Mukhopadhyay, Anandaroop ; Lee, Younjee ; Schuman, Sophia S. ; Guthrie, Matthew R. ; Berrett, Kristofer C. ; Vahrenkamp, Jeffery M. ; Hu, Zeping ; Kudla, Marek ; Modzelewska, Katarzyna ; Wang, Guoying ; Ingolia, Nicholas T. ; Gertz, Jason ; Lum, David H. ; Cosulich, Sabina C. ; Bomalaski, John S. ; DeBerardinis, Ralph J ; Oliver, Trudy G. / MYC-driven small-cell lung cancer is metabolically distinct and vulnerable to arginine depletion. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 16. pp. 5107-5121.
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title = "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 MYCL-driven 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 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-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.",
author = "Chalishazar, {Milind D.} and Wait, {Sarah J.} and Fang Huang and Ireland, {Abbie S.} and Anandaroop Mukhopadhyay and Younjee Lee and Schuman, {Sophia S.} and Guthrie, {Matthew R.} and Berrett, {Kristofer C.} and Vahrenkamp, {Jeffery M.} and Zeping Hu and Marek Kudla and Katarzyna Modzelewska and Guoying Wang and Ingolia, {Nicholas T.} and Jason Gertz and Lum, {David H.} and Cosulich, {Sabina C.} and Bomalaski, {John S.} and DeBerardinis, {Ralph J} and Oliver, {Trudy G.}",
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TY - JOUR

T1 - MYC-driven small-cell lung cancer is metabolically distinct and vulnerable to arginine depletion

AU - Chalishazar, Milind D.

AU - Wait, Sarah J.

AU - Huang, Fang

AU - Ireland, Abbie S.

AU - Mukhopadhyay, Anandaroop

AU - Lee, Younjee

AU - Schuman, Sophia S.

AU - Guthrie, Matthew R.

AU - Berrett, Kristofer C.

AU - Vahrenkamp, Jeffery M.

AU - Hu, Zeping

AU - Kudla, Marek

AU - Modzelewska, Katarzyna

AU - Wang, Guoying

AU - Ingolia, Nicholas T.

AU - Gertz, Jason

AU - Lum, David H.

AU - Cosulich, Sabina C.

AU - Bomalaski, John S.

AU - DeBerardinis, Ralph J

AU - Oliver, Trudy G.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - 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-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 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-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.

AB - 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-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 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-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.

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