CDK4/6 and Autophagy Inhibitors Synergistically Induce Senescence in Rb Positive Cytoplasmic Cyclin E Negative Cancers

Nat Commun. 2017 Jun 27;8:15916. doi: 10.1038/ncomms15916.

Abstract

Deregulation of the cell cycle machinery is a hallmark of cancer. While CDK4/6 inhibitors are FDA approved (palbociclib) for treating advanced estrogen receptor-positive breast cancer, two major clinical challenges remain: (i) adverse events leading to therapy discontinuation and (ii) lack of reliable biomarkers. Here we report that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumours in vivo. Furthermore, intact G1/S transition (Rb-positive and low-molecular-weight isoform of cyclin E (cytoplasmic)-negative) is a reliable prognostic biomarker in ER positive breast cancer patients, and predictive of preclinical sensitivity to this drug combination. Inhibition of CDK4/6 and autophagy is also synergistic in other solid cancers with an intact G1/S checkpoint, providing a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumours.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Autophagy / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / physiopathology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cellular Senescence / drug effects
  • Cyclin E / genetics
  • Cyclin E / metabolism*
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclin-Dependent Kinase 6 / metabolism
  • Cytoplasm / drug effects
  • Cytoplasm / genetics
  • Cytoplasm / metabolism
  • Drug Synergism
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Piperazines / administration & dosage*
  • Protein Kinase Inhibitors / administration & dosage*
  • Pyridines / administration & dosage*
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism*

Substances

  • Antineoplastic Agents
  • Cyclin E
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Retinoblastoma Protein
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • palbociclib