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.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
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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U2 - 10.1158/1078-0432.CCR-18-4140
DO - 10.1158/1078-0432.CCR-18-4140
M3 - Article
C2 - 31164374
AN - SCOPUS:85070694131
SN - 1078-0432
VL - 25
SP - 5107
EP - 5121
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -