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

AbstractBACKGROUND 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.
AuthorsHelen Zhao, Kaisa R Luoto, Alice X Meng, Robert G Bristow
JournalRadiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 101 Issue 1 Pg. 59-65 (Oct 2011) ISSN: 1879-0887 [Electronic] Ireland
PMID21903282 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Piperazines
  • Pyrimidines
  • Radiation-Sensitizing Agents
  • Receptor Protein-Tyrosine Kinases
  • Rad51 Recombinase
  • Thiourea
  • amuvatinib
Topics
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Homologous Recombination (drug effects, genetics, radiation effects)
  • Humans
  • Lung Neoplasms (drug therapy, genetics, radiotherapy)
  • Phosphorylation
  • Piperazines
  • Pyrimidines (pharmacology)
  • Rad51 Recombinase (drug effects, genetics, radiation effects)
  • Radiation Tolerance (drug effects)
  • Radiation, Ionizing
  • Radiation-Sensitizing Agents (pharmacology)
  • Real-Time Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
  • Thiourea
  • Tumor Cells, Cultured

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