Antiproliferative effects of EGFR tyrosine kinase inhibition and radiation-induced genotoxic injury are attenuated by adhesion to fibronectin.

Abstract

Integrin-linked kinase (ILK) functions in cooperative integrin-growth factor receptor-mediated signaling to control cell survival and proliferation. The effect of tyrosine kinase (tk) inhibition of the epidermal growth factor receptor (EGFR) on radiation survival and growth was evaluated in human FaDu squamous cell carcinoma cells expressing different forms of ILK. ILK-wild-type (wk) and -hyperactive kinase (hk) transfected cells were grown on fibronectin (Fn) under serum presence or depletion, irradiated (0-6Gy) and/or treated with the EGFR-tk inhibitor BIBX1382BS. ILK-wk and -hk transfectants showed significant radiosensitization compared to vector control cells. Antisurvival and antiproliferative effects of EGFR-tk inhibition plus/minus irradiation were counteracted by adhesion to Fn relative to the control substratum, poly-L-lysine. Similar to vector controls, ILK transfectants exhibited a strong decrease in cell proliferation but no enhanced radiation sensitivity after EGFR-tk inhibition. This decrease was accompanied by changes in cyclin D1 and phosphorylated MAPK persisting to day 10 following transient drug exposure. Our data demonstrate a prosurvival role of adhesion and an antisurvival role of ILK upon irradiation. Inhibition of EGFR-tk using BIBX1382BS does not affect the intrinsic cellular radiosensitivity of cells grown on fibronectin. Thus, simultaneous targeting of adhesion and growth factor receptor-mediated signaling might potently improve anticancer strategies.