Cell-Cycle Position of Single MYC-Driven Cancer Cells Dictates Their Susceptibility to a Chemotherapeutic Drug

Cell Syst. 2017 Sep 27;5(3):237-250.e8. doi: 10.1016/j.cels.2017.07.005. Epub 2017 Aug 23.


While many tumors initially respond to chemotherapy, regrowth of surviving cells compromises treatment efficacy in the long term. The cell-biological basis of this regrowth is not understood. Here, we characterize the response of individual, patient-derived neuroblastoma cells driven by the prominent oncogene MYC to the first-line chemotherapy, doxorubicin. Combining live-cell imaging, cell-cycle-resolved transcriptomics, and mathematical modeling, we demonstrate that a cell's treatment response is dictated by its expression level of MYC and its cell-cycle position prior to treatment. All low-MYC cells enter therapy-induced senescence. High-MYC cells, by contrast, disable their cell-cycle checkpoints, forcing renewed proliferation despite treatment-induced DNA damage. After treatment, the viability of high-MYC cells depends on their cell-cycle position during treatment: newborn cells promptly halt in G1 phase, repair DNA damage, and form re-growing clones; all other cells show protracted DNA repair and ultimately die. These findings demonstrate that fast-proliferating tumor cells may resist cytotoxic treatment non-genetically, by arresting within a favorable window of the cell cycle.

Keywords: MYC; bistability; cancer; cell-cycle checkpoints; cell-cycle-resolved transcriptomics; live-cell imaging; mathematical modeling; therapy resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • DNA Damage / drug effects
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Models, Theoretical
  • Neuroblastoma / genetics
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-myc / genetics*
  • Transcriptome / genetics


  • Proto-Oncogene Proteins c-myc
  • Doxorubicin