In spite of significant technical advances including IMRT and chemoradiation, locally advanced lung cancer continues to have a dismal prognosis as many patients’ tumors appear to be resistant to radiation therapy. The need to improve the result of radiation therapy presents an opportunity to evaluate molecular targeting strategies for sensitizing NSCLC to radiation. It is well established that EGFR is constitutively activated in many human, non-small cell lung cancers (NSCLC) and that this activation correlates with a radioresistant phenotype. Thus, the response of NSCLC to radiation may be improved through the use of inhibitors of EGFR signaling. Several novel agents that target various steps in this pathway are currently available for testing this hypothesis.
In the present study, we report the effects of Tarceva (Erlotinib, OSI-774), a selective EGFR tyrosine kinase inhibitor, and C225 (Erbitux, Cetuximab) a monoclonal antibody to the EGF receptor, on the radiation sensitivity of three NSCLC cell lines, A549, H460 and H1299, that express moderate to high levels of the EGFR. Clonogenic cell survival assays showed that Tarceva significantly radiosensitized all three NSCLC cell lines, substantially reducing the surviving fraction at 2 Gy (SF2). Pre-treatment with 5 μM Tarceva for 24 hr enhanced tumor cell radiosensitivity with the survival factor at 2Gy (SF2) being reduced from 61.5%, 78% and 56% in vehicle-treated to 37.9%, 56% and 52% in Tarceva-treated A549, H460 and H1299 cells respectively. Similarly, pre-treatment with 30nM C225 for 1 hr radiosensitized both H1299 and A549 cells with SF2 being reduced from 72% and 44.2% in vehicle-treated to 54.9% and 16% in C225 treated A549 and H1299 cells respectively. Both agents had a radioprotective effect on normal human lung fibroblasts. We examined potential mechanisms that may contribute to the enhanced radiation response induced by Tarceva and C225. Dose-dependent decreases in pEGFR were evident following treatment with Tarceva and C225 in H1299 cells. C225 blocked constitutive and radiation-induced activation of pERK in A549 cells possibly correlating with its radiosensitizing effects. Overall, our results suggest that both Tarceva and C225 synergistically interact with radiation and enhance the radioresponse of human NSCLC cells. A detailed investigation of the mechanism is ongoing. The insight gained from the analyses of these molecular mechanisms will be very useful in future research examining the combination of molecular targeted agents such as Tarceva and C225 and ionizing radiation
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA