MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity

Genes Dev. 2020 Sep 1;34(17-18):1210-1226. doi: 10.1101/gad.340133.120. Epub 2020 Aug 20.


Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. In treatment-naïve mice, MYCN overexpression promoted cell cycle progression, suppressed infiltration of cytotoxic T cells, and accelerated SCLC. MYCN overexpression also suppressed response to cisplatin-etoposide chemotherapy, with similar findings made upon MYCL overexpression. We extended these data to genetically perturb chemosensitive patient-derived xenograft (PDX) models of SCLC. In chemosensitive PDX models, overexpression of either MYCN or MYCL also conferred a switch to chemoresistance. To identify therapeutic strategies for MYCN-overexpressing SCLC, we performed a genome-scale CRISPR-Cas9 sgRNA screen. We identified the deubiquitinase USP7 as a MYCN-associated synthetic vulnerability. Pharmacological inhibition of USP7 resensitized chemoresistant MYCN-overexpressing PDX models to chemotherapy in vivo. Our findings show that MYCN overexpression drives SCLC chemoresistance and provide a therapeutic strategy to restore chemosensitivity.

Keywords: MYCL; MYCN; SCLC; USP7; chemoresistance.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Heterografts
  • Humans
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics*
  • Mice
  • N-Myc Proto-Oncogene Protein / genetics
  • N-Myc Proto-Oncogene Protein / metabolism*
  • Small Cell Lung Carcinoma / enzymology
  • Small Cell Lung Carcinoma / genetics
  • Ubiquitin-Specific Peptidase 7 / metabolism*


  • Enzyme Inhibitors
  • N-Myc Proto-Oncogene Protein
  • Ubiquitin-Specific Peptidase 7