Journal
RADIOTHERAPY AND ONCOLOGY
Volume 124, Issue 3, Pages 370-378Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.radonc.2017.05.011
Keywords
Beta1-integrin; c-Abl; Imatinib; Ionizing radiation; DNA-repair
Funding
- Else-Kroner Fresenius Stiftung [060_380624]
- Deutsche Krebshilfe [108976]
- EFRE Europaische Fonds fur regionale Entwicklung, Europa fordert Sachsen [100066308]
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Integrin-mediated cell adhesion to extracellular matrix (ECM) critically contributes to cancer cell therapy resistance and DNA double strand break (DSB) repair. c-Abl tyrosine kinase has been linked to both of these processes. Based on our previous findings indicating c-Abl hyperphosphorylation on tyrosine (Y) 412 and threonine (T) 735 upon betal-integrin inhibition, we hypothesized c-Abl tyrosine kinase as an important mediator of betal-integrin signaling for radioresistance. In a panel of 8 cell lines from different solid cancer types grown in 3D laminin-rich ECM cultures, we targeted betal integrin with AIIB2 (mAb) and c-Abl with Imatinib with and without X-ray irradiation and subsequently examined clonogenic survival, residual DSBs, protein expression and phosphorylation. Single or combined treatment with AIIB2 and Imatinib resulted in cell line-dependent cytotoxicity. Intriguingly, we identified a subgroup of this cell line panel that responded with a higher degree of radiosensitization to AIIB2/Imatinib relative to both single treatments. In this subgroup, we observed a non-statistically significant trend between the radioresponse and phospho-c-Abl Y412. Mechanistically, impairment of DNA repair seems to be associated with radiosensitization upon AIIB2/Imatinib and AIIB2/Imatinib-related radiosensitization could be reduced by exogenous overexpression of either wildtype or constitutively active c-Abl forms relative to controls. Our data generated in more physiological 3D cancer cell culture models suggest c-Abl as further determinant of radioresistance and DNA repair downstream of betal-integrin. For solid cancers, c-Abl phosphorylation status might be an indicator for reasonable Imatinib application as adjuvant for conventional radio(chemo)therapy. (C) 2017 Elsevier B.V. All rights reserved.
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