P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: Implication in cancer therapy

Cancer Lett. 2019 Jun 1:451:23-33. doi: 10.1016/j.canlet.2019.02.049. Epub 2019 Mar 11.

Abstract

Targeting cell cycle has become one of the major challenges in cancer therapy, being Palbociclib, a CDK4/6 inhibitor, an excellent example. Recently, it has been reported that Palbociclib could be a novel radiosensitizer agent. In an attempt to clarify the molecular basis of this effect we have used cell lines from colorectal (HT29, HCT116) lung (A549, H1299) and breast cancer (MCF-7). Our results indicate that the presence of a p53 wild type is strictly required for Palbociclib to exert its radiosensitizing effect, independently of the inhibitory effect exerted on CDK4/6. In fact, abrogation of p53 in cells with functional p53 blocks the radiosensitizing effect of Palbociclib. Moreover, no radiosensitizing effect is observed in cells with non-functional p53, but restoration of p53 function promotes radiosensitivity associated to Palbociclib. Furthermore, the presence of Palbociclib blocks the transcriptional activity of p53 in an ATM-dependent-fashion after ionizing radiation exposure, as the blockage of p21/WAF1 expression demonstrates. These observations are a proof of concept for a more selective therapy, based on the combination of CDK4/6 inhibition and radiotherapy, which would only benefit to those patients with a functional p53 pathway.

Keywords: ATM; CDK4/6; Palbociclib; Radiosensitivity; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Humans
  • Piperazines / pharmacology*
  • Pyridines / pharmacology*
  • Radiation-Sensitizing Agents / pharmacology*
  • Signal Transduction / drug effects
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Piperazines
  • Pyridines
  • Radiation-Sensitizing Agents
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • palbociclib