MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

Nat Commun. 2019 Aug 2;10(1):3485. doi: 10.1038/s41467-019-11371-x.


MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • CRISPR-Cas Systems / genetics
  • Cell Line, Tumor
  • DNA Damage / drug effects
  • DNA Damage / genetics
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics*
  • HEK293 Cells
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Mice
  • Molecular Targeted Therapy / methods
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA, Small Interfering / metabolism
  • Small Cell Lung Carcinoma / drug therapy
  • Small Cell Lung Carcinoma / genetics*


  • Antineoplastic Agents
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering