title: The receptor tyrosine kinase inhibitor amuvatinib (MP470) sensitizes tumor cells to radio- and chemo-therapies in part by inhibiting homologous recombination.
abstract: OBJECTIVE
  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.
  
  
  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.
authors: Campbell Family Cancer Research Institute, University of Toronto, Ontario, Canada.
authors: Helen
authors: H
authors: Zhao
authors: Kaisa R
authors: KR
authors: Luoto
authors: Alice X
authors: AX
authors: Meng
authors: Robert G
authors: RG
authors: Bristow
mesh_terms: D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D059765:Homologous Recombination / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D010766:Phosphorylation; D010879:Piperazines; D011743:Pyrimidines / Q000494:pharmacology*; D051135:Rad51 Recombinase / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013890:Thiourea; D014407:Tumor Cells, Cultured
chemical_list: D010879:Piperazines; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D020794:Receptor Protein-Tyrosine Kinases; D051135:Rad51 Recombinase; D013890:Thiourea; C521047:amuvatinib