Protein neddylation as a therapeutic target in pulmonary and extrapulmonary small cell carcinomas

Genes Dev. 2021 Jun;35(11-12):870-887. doi: 10.1101/gad.348316.121. Epub 2021 May 20.

Abstract

Small cell lung carcinoma (SCLC) is among the most lethal of all solid tumor malignancies. In an effort to identify novel therapeutic approaches for this recalcitrant cancer type, we applied genome-scale CRISPR/Cas9 inactivation screens to cell lines that we derived from a murine model of SCLC. SCLC cells were particularly sensitive to the deletion of NEDD8 and other neddylation pathway genes. Genetic suppression or pharmacological inhibition of this pathway using MLN4924 caused cell death not only in mouse SCLC cell lines but also in patient-derived xenograft (PDX) models of pulmonary and extrapulmonary small cell carcinoma treated ex vivo or in vivo. A subset of PDX models were exceptionally sensitive to neddylation inhibition. Neddylation inhibition suppressed expression of major regulators of neuroendocrine cell state such as INSM1 and ASCL1, which a subset of SCLC rely upon for cell proliferation and survival. To identify potential mechanisms of resistance to neddylation inhibition, we performed a genome-scale CRISPR/Cas9 suppressor screen. Deletion of components of the COP9 signalosome strongly mitigated the effects of neddylation inhibition in small cell carcinoma, including the ability of MLN4924 to suppress neuroendocrine transcriptional program expression. This work identifies neddylation as a regulator of neuroendocrine cell state and potential therapeutic target for small cell carcinomas.

Keywords: cancer; neuroendocrine; small cell lung cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • COP9 Signalosome Complex / genetics
  • Carcinoma, Small Cell / physiopathology
  • Carcinoma, Small Cell / therapy*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cyclopentanes* / pharmacology
  • Cyclopentanes* / therapeutic use
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterografts
  • Humans
  • Lung Neoplasms / physiopathology
  • Lung Neoplasms / therapy*
  • Mice
  • NEDD8 Protein / genetics
  • NEDD8 Protein / metabolism*
  • Neuroendocrine Cells / cytology
  • Neuroendocrine Cells / drug effects
  • Proteins / genetics
  • Proteins / metabolism
  • Pyrimidines* / pharmacology
  • Pyrimidines* / therapeutic use
  • Repressor Proteins / genetics
  • Sequence Deletion

Substances

  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Cyclopentanes
  • NEDD8 Protein
  • Proteins
  • Pyrimidines
  • Repressor Proteins
  • INSM1 protein, human
  • COP9 Signalosome Complex
  • pevonedistat