The receptor tyrosine kinase inhibitor amuvatinib (MP470) sensitizes tumor cells to radio- and chemo-therapies in part by inhibiting homologous recombination

Radiother Oncol. 2011 Oct;101(1):59-65. doi: 10.1016/j.radonc.2011.08.013. Epub 2011 Sep 6.

Abstract

Background and purpose: RAD51 is a key protein involved in homologous recombination (HR) and a potential target for radiation- and chemotherapies. Amuvatinib (formerly known as MP470) is a novel receptor tyrosine kinase inhibitor that targets c-KIT and PDGFRα and can sensitize tumor cells to ionizing radiation (IR). Here, we studied amuvatinib mechanism on RAD51 and functional HR.

Materials and methods: Protein and RNA analyses, direct repeat green fluorescent protein (DR-GFP) assay and polysomal fractioning were used to measure HR efficiency and global translation in amuvatinib-treated H1299 lung carcinoma cells. Synergy of amuvatinib with IR or mitomycin c (MMC) was assessed by clonogenic survival assay.

Results: Amuvaninib inhibited RAD51 protein expression and HR. This was associated with reduced ribosomal protein S6 phosphorylation and inhibition of global translation. Amuvatinib sensitized cells to IR and MMC, agents that are selectively toxic to HR-deficient cells.

Conclusions: Amuvatinib is a promising agent that may be used to decrease tumor cell resistance. Our work suggests that this is associated with decreased RAD51 expression and function and supports the further study of amuvatinib in combination with chemotherapy and radiotherapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Homologous Recombination / drug effects*
  • Homologous Recombination / genetics
  • Homologous Recombination / radiation effects
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / radiotherapy*
  • Phosphorylation
  • Pyrimidines / pharmacology*
  • Rad51 Recombinase / drug effects
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / radiation effects
  • Radiation Tolerance / drug effects*
  • Radiation, Ionizing
  • Radiation-Sensitizing Agents / pharmacology*
  • Real-Time Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Tumor Cells, Cultured

Substances

  • MP470
  • Pyrimidines
  • Radiation-Sensitizing Agents
  • Receptor Protein-Tyrosine Kinases
  • Rad51 Recombinase