Inosine Monophosphate Dehydrogenase Dependence in a Subset of Small Cell Lung Cancers

Abstract

Small cell lung cancer (SCLC) is a rapidly lethal disease with few therapeutic options. We studied metabolic heterogeneity in SCLC to identify subtype-selective vulnerabilities. Metabolomics in SCLC cell lines identified two groups correlating with high or low expression of the Achaete-scute homolog-1 (ASCL1) transcription factor (ASCL1 and ASCL1), a lineage oncogene. Guanosine nucleotides were elevated in ASCL1 cells and tumors from genetically engineered mice. ASCL1 tumors abundantly express the guanosine biosynthetic enzymes inosine monophosphate dehydrogenase-1 and -2 (IMPDH1 and IMPDH2). These enzymes are transcriptional targets of MYC, which is selectively overexpressed in ASCL1 SCLC. IMPDH inhibition reduced RNA polymerase I-dependent expression of pre-ribosomal RNA and potently suppressed ASCL1 cell growth in culture, selectively reduced growth of ASCL1 xenografts, and combined with chemotherapy to improve survival in genetic mouse models of ASCL1/MYC SCLC. The data define an SCLC subtype-selective vulnerability related to dependence on de novo guanosine nucleotide synthesis.

A metabolic vulnerability of small-cell lung cancer

“…SCLC cell dependency on high PK activity appears much greater than that of other cancer types, suggesting that SCLC cells have unique metabolic properties and are particularly vulnerable to down-modulation of PK activity. Relevant to this, Huang F. et al recently reported an interesting metabolic feature of SCLC, namely, inosine monophosphate dehydrogenase dependence, although this property was only seen in a minor subset (ASCL1 low ) of these cancers [10]. Better understanding of SCLC cell metabolism is needed to devise novel therapeutic strategies to treat this aggressive malignancy, which harbors few druggable mutations.…”

Leveraging insights into cancer metabolism—a symposium report

“…Steady‐state metabolomic profiling in collaboration with Ralph DeBerardinis's laboratory has shown that C‐MYC–driven tumors are metabolically distinct from L‐MYC–driven tumors . C‐MYC–driven tumors show an enrichment in nucleotide biosynthesis and arginine metabolism .…”

“…Their expression levels can be used to define SCLC molecular subsets that have distinct metabolic profiles. In SCLC cell lines as well as tissue samples from treatment‐naive patients, ASCL1 low /C‐MYC high tumors had abundant purine nucleotides …”

“…Inhibition of IMPDH suppressed tumor growth in ASCL1 low /C‐MYC high mouse xenografts, but not ASCL1 high /C‐MYC low xenografts. In a genetic mouse model of C‐MYC high SCLC, IMPDH inhibition alone modestly improved survival, while the combination of IMPDH inhibition and chemotherapy showed synergistic effects …”

“…DeBerardinis provided new evidence that cell lines derived from relapsed patients were more likely to have enhanced expression of both C‐MYC and IMPDH, and increased GTP synthesis. Furthermore, selecting for chemotherapy resistance in culture caused cells to acquire the sensitivity to IMDPH inhibition in vivo …”