Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs

Cell Death Differ. 2015 Dec;22(12):1946-56. doi: 10.1038/cdd.2015.59. Epub 2015 May 29.

Abstract

Polo-like kinase 1 (PLK1) is frequently overexpressed in cancer, which correlates with poor prognosis. Therefore, we investigated PLK1 as therapeutic target using rhabdomyosarcoma (RMS) as a model. Here, we identify a novel synthetic lethal interaction of PLK1 inhibitors and microtubule-destabilizing drugs in preclinical RMS models and elucidate the underlying molecular mechanisms of this synergism. PLK1 inhibitors (i.e., BI 2536 and BI 6727) synergistically induce apoptosis together with microtubule-destabilizing drugs (i.e., vincristine (VCR), vinblastine (VBL) and vinorelbine (VNR)) in several RMS cell lines (combination index <0.9) including a patient-derived primary RMS culture. Importantly, PLK1 inhibitors and VCR cooperate to significantly suppress RMS growth in two in vivo models, including a mouse xenograft model, without causing additive toxicity. In addition, no toxicity was observed in non-malignant fibroblast or myoblast cultures. Mechanistically, BI 2536/VCR co-treatment triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by BAX/BAK activation, production of reactive oxygen species (ROS) and activation of caspase-dependent or caspase-independent effector pathways. This conclusion is supported by data showing that BI 2536/VCR-induced apoptosis is significantly inhibited by preventing cells to enter mitosis, by overexpression of BCL-2 or a non-degradable MCL-1 mutant, by BAK knockdown, ROS scavengers, caspase inhibition or endonuclease G silencing. This identification of a novel synthetic lethality of PLK1 inhibitors and microtubule-destabilizing drugs has important implications for developing PLK1 inhibitor-based combination treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Disease Models, Animal
  • Drug Synergism
  • Humans
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Protein Kinase Inhibitors / toxicity*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pteridines / toxicity*
  • Reactive Oxygen Species / metabolism
  • Rhabdomyosarcoma / metabolism
  • Rhabdomyosarcoma / pathology
  • Signal Transduction / drug effects
  • Transplantation, Heterologous
  • Tubulin Modulators / toxicity*
  • Tumor Cells, Cultured
  • bcl-2 Homologous Antagonist-Killer Protein / antagonists & inhibitors
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism

Substances

  • BI 2536
  • BI 6727
  • Cell Cycle Proteins
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pteridines
  • Reactive Oxygen Species
  • Tubulin Modulators
  • bcl-2 Homologous Antagonist-Killer Protein
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1