Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

PURPOSE: To evaluate the combination of radiation and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in preclinical models of human non-small cell lung cancer. METHODS AND MATERIALS: Sensitivity to an EGFR TKI (gefitinib) or radiation was assessed using proliferation assays and clonogenic survival assays. Effects on receptor signal transduction pathways (pEGFR, pAKT, pMAPK) and apoptosis (percentage of cleaved PARP Poly (ADP-ribose) polymerase (PARP)) were assessed by Western blotting. Radiation-induced DNA damage was assessed by γH2AX immunofluorescence. Established (≥ 100 mm(3)) EGFR-mutated (HCC287) or EGFR wild-type (A549) subcutaneous xenografts were treated with radiation (10 Gy, day 1) or gefitinib (50 mg/kg, orally, on days 1-3) or both. RESULTS: In non-small cell lung cancer (NSCLC) cell lines with activating EGFR mutations (PC9 or HCC827), gefitinib treatment markedly reduced pEGFR, pAKT, and pMAPK levels and was associated with an increase in cleaved PARP but not in γH2AX foci. Radiation treatment increased the mean number of γH2AX foci per cell but did not significantly affect EGFR signaling. In contrast, NSCLC cell lines with EGFR T790M (H1975) or wild-type EGFR (A549) were insensitive to gefitinib treatment. The combination of gefitinib and radiation treatment in cell culture produced additive cell killing with no evidence of synergy. In xenograft models, a short course of gefitinib (3 days) did not significantly increase the activity of radiation treatment in wild-type EGFR (A549) tumors (P=.27), whereas this combination markedly increased the activity of radiation (P<.001) or gefitinib alone (P=.002) in EGFR-mutated HCC827 tumors, producing sustained tumor regressions. CONCLUSIONS: Gefitinib treatment increases clonogenic cell killing by radiation but only in cell lines sensitive to gefitinib alone. Our data suggest additive rather than synergistic interactions between gefitinib and radiation and that a combination of short-course gefitinib and high-dose/-fraction radiation may have the greatest potential against the subsets of lung cancers harboring activating mutations in the EGFR gene.

Original publication

DOI

10.1016/j.ijrobp.2013.12.038

Type

Journal article

Journal

Int J Radiat Oncol Biol Phys

Publication Date

15/03/2014

Volume

88

Pages

947 - 954

Keywords

Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Combined Modality Therapy, Disease Models, Animal, ErbB Receptors, Gefitinib, Genes, erbB-1, Heterografts, Histones, Humans, Lung Neoplasms, Mice, Mitogen-Activated Protein Kinase Kinases, Poly(ADP-ribose) Polymerases, Proto-Oncogene Proteins c-akt, Quinazolines, Xenograft Model Antitumor Assays