Imatinib Radiosensitizes Bladder Cancer by Targeting Homologous Recombination

Boling Qiao, Martin Kerr, Blaz Groselj, Mark T W Teo, Margaret A. Knowles, Robert G. Bristow, Roger M. Phillips, Anne E. Kiltie

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Radiotherapy is a major treatment modality used to treat muscle-invasive bladder cancer, with patient outcomes similar to surgery. However, radioresistance is a significant factor in treatment failure. Cell-free extracts of muscle-invasive bladder tumors are defective in nonhomologous end-joining (NHEJ), and this phenotype may be used clinically by combining radiotherapy with a radiosensitizing drug that targets homologous recombination, thereby sparing normal tissues with intact NHEJ. The response of the homologous recombination protein RAD51 to radiation is inhibited by the small-molecule tyrosine kinase inhibitor imatinib. Stable RT112 bladder cancer Ku knockdown (Ku80KD) cells were generated using short hairpin RNA technology to mimic the invasive tumor phenotype and also RAD51 knockdown (RAD51KD) cells to show imatinib's pathway selectivity. Ku80KD, RAD51KD, nonsilencing vector control, and parental RT112 cells were treated with radiation in combination with either imatinib or lapatinib, which inhibits NHEJ and cell survival assessed by clonogenic assay. Drug doses were chosen at approximately IC40 and IC10 (nontoxic) levels. Imatinib radiosensitized Ku80KD cells to a greater extent than RAD51KD or RT112 cells. In contrast, lapatinib radiosensitized RAD51KD and RT112 cells but not Ku80KD cells. Taken together, our findings suggest a new application for imatinib in concurrent use with radiotherapy to treat muscle-invasive bladder cancer.

Original languageEnglish
Pages (from-to)1611-1620
Number of pages10
JournalCancer Research
Volume73
Issue number5
Early online date9 Jan 2013
DOIs
Publication statusPublished - Mar 2013
Externally publishedYes

Fingerprint

Homologous Recombination
Urinary Bladder Neoplasms
Radiotherapy
Muscles
Rad51 Recombinase
Radiation
Radiation-Sensitizing Agents
Phenotype
Imatinib Mesylate
Cell Extracts
Treatment Failure
Protein-Tyrosine Kinases
Small Interfering RNA
Cell Survival
Technology
Pharmaceutical Preparations
Neoplasms

Cite this

Qiao, B., Kerr, M., Groselj, B., Teo, M. T. W., Knowles, M. A., Bristow, R. G., ... Kiltie, A. E. (2013). Imatinib Radiosensitizes Bladder Cancer by Targeting Homologous Recombination. Cancer Research, 73(5), 1611-1620. https://doi.org/10.1158/0008-5472.CAN-12-1170
Qiao, Boling ; Kerr, Martin ; Groselj, Blaz ; Teo, Mark T W ; Knowles, Margaret A. ; Bristow, Robert G. ; Phillips, Roger M. ; Kiltie, Anne E. / Imatinib Radiosensitizes Bladder Cancer by Targeting Homologous Recombination. In: Cancer Research. 2013 ; Vol. 73, No. 5. pp. 1611-1620.
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Qiao, B, Kerr, M, Groselj, B, Teo, MTW, Knowles, MA, Bristow, RG, Phillips, RM & Kiltie, AE 2013, 'Imatinib Radiosensitizes Bladder Cancer by Targeting Homologous Recombination', Cancer Research, vol. 73, no. 5, pp. 1611-1620. https://doi.org/10.1158/0008-5472.CAN-12-1170

Imatinib Radiosensitizes Bladder Cancer by Targeting Homologous Recombination. / Qiao, Boling; Kerr, Martin; Groselj, Blaz; Teo, Mark T W; Knowles, Margaret A.; Bristow, Robert G.; Phillips, Roger M.; Kiltie, Anne E.

In: Cancer Research, Vol. 73, No. 5, 03.2013, p. 1611-1620.

Research output: Contribution to journalArticle

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Qiao B, Kerr M, Groselj B, Teo MTW, Knowles MA, Bristow RG et al. Imatinib Radiosensitizes Bladder Cancer by Targeting Homologous Recombination. Cancer Research. 2013 Mar;73(5):1611-1620. https://doi.org/10.1158/0008-5472.CAN-12-1170