| Description |
Small cell lung cancer (SCLC) is a neuroendocrine subtype of lung cancer characterized by aggressive growth, widespread metastasis, and inevitable chemotherapy resistance with limited treatments available. Clinically, SCLC patients exhibit an average survival of 6-10 months with less than 6% of the patients surviving over two years. Combination chemotherapy (mainly cisplatin and etoposide) has been the standard of care for SCLC, and this regimen has not changed substantially in over 40 years. Newer approaches are urgently needed for more effective therapeutic strategies in SCLC. SCLC has been treated as a homogeneous disease, but recent discoveries suggest that SCLC consists of distinct molecular subtypes, driven notably by distinct MYC family members. With our collaborators, we performed steady-state metabolomics on tumors isolated from genetically-engineered mouse models (GEMMs) and human cell lines representing the MYC and MYCL-driven subtypes of SCLC. We discovered that SCLC subtypes driven by distinct MYC family members have distinct metabolic profiles. Using functional studies, we find that MYC-driven SCLC depends on inosine monophosphate dehydrogenase-1 and -2 (IMPDH1 and IMPDH2) for guanosine biosynthesis and on arginine biosynthesis for polyamine generation and mTOR pathway activation. IMPDH1/2 inhibition using mizoribine selectively hindered the iv growth of a MYC-driven GEMM of SCLC. Arginine depletion using pegylated arginine deiminase (ADI-PEG 20) strikingly suppressed tumor growth and promoted survival of mice specifically with MYC-driven tumors including in GEMMs, cell line xenografts, and a chemoresistant patient-derived xenograft (PDX). Our unpublished data suggest that MYC inversely correlates with expression of the mitochondrial pyruvate carriers (MPC), MPC1/2 in SCLC cell lines and mouse models. Downregulation of MPC1/2 in MYC-driven SCLC is associated with increased glycolysis. Altogether, these findings suggest that MYCdriven SCLC requires glycolysis and nucleotide biosynthesis for its rapid and aggressive growth. Moreover, these data suggest that metabolic vulnerabilities exist between SCLC subtypes that can be therapeutically targeted using clinically relevant agents. |
