Enhancement of Radiosensitivity in Head and Neck Cancer Cells by ZD1839 (‘IRESSA’), A Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Abstract

Overexpression of epidermal growth factor receptor (EGFR) is frequently observed in many solid tumor types, including head and neck squamous cell carcinomas (HNSCC). Recent laboratory experiments have demonstrated that high EGFR levels correlate with increased tumor resistance to radiation. This study investigated the relationship between EGFR expression levels and radiosensitivity in 5 HNSCC cell lines (HSC2, HSC3, HSC4, SCC25, and Ca9-22) and whether treatment with ZD1839 ('Iressa'), a selective EGFR-tyrosine kinase inhibitor (TKI), would improve tumor cell response to radiotherapy. ZD1839 suppressed the growth of HNSCC cell lines in a dose- and time-dependent manner. Radiosensitivity of these HNSCC cell lines, assessed by a clonogenic survival assay, differed greatly and the expression of EGFR varied. EGFR expression levels (EGFR numbers/cell) correlated with increased tumor resistance to radiation (f[x]= 4.54 X, R2 = 0.715; f[x]: EGFR numbers/cell, X: radiosensitivity; D10). Following exposure of the HNSCC cells to 1.0 microM ZD1839 and radiation (0-10 Gy), greater than additive growth inhibitory effects were observed. These results suggest that ZD1839 could enhance tumor radiosensitivity and inhibit tumor growth after radiation, indicating that this combination could have clinical potential in the treatment of patients with head and neck cancer.

Pre-Clinical Characterization of Dacomitinib (PF-00299804), an Irreversible Pan-ErbB Inhibitor, Combined with Ionizing Radiation for Head and Neck Squamous Cell Carcinoma

“…Ionizing radiation alone can induce EGFR activation, through increased expression of either EGFR or its ligand TGF-α, which may then lead to a proliferative response [37]. Other EGFR inhibitors have been combined with IR, all consistently supporting this combinatorial strategy for anti-tumor efficacy [38]–[40]. Multiple mechanisms of radio-sensitization by EGFR inhibition have been described, including cell cycle perturbation [41], inhibition of DNA damage repair [42], as well as an anti-angiogenic effects [43].…”

Breast Cancer Expressing the Activated HER2/neu Is Sensitive to Gefitinib In vitro and In vivo and Acquires Resistance through a Novel Point Mutation in the HER2/neu

“…In vitro, the effect of gefitinib on human breast, ovarian, and colon cell lines expressing various amounts of EGFR and/or HER2 has been described as mainly cytostatic with increasing apoptotic activity at the higher doses (14,15). Supra-additive antiproliferative effects were observed with a broad range of cytotoxics (12,16) and radiation (17) in vitro and in vivo. The efficacy of gefitinib in HER2-overexpressing human breast cancer cell lines has been described and seems to be contingent upon the expression levels of both HER2 and EGFR as well as the degree to which these receptors are coupled to the growth [mitogen-activated protein kinase (MAPK)] and survival (Akt) pathways (14,15).…”

EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids

“…EGFR is an attractive therapeutic target because EGFR mutations associated with response to TK inhibitors (gefitinib or erlotinib) are identified in 10-40% of patients (depending on ethnicity) with non-small cell lung cancer (NSCLC) (Lynch et al, 2004;Paez et al, 2004;Shigematsu and Gazdar, 2005a). Cells with EGFR mutations are relatively resistant to apoptosis induced by conventional chemotherapeutic drugs and radiation therapy, but undergo extensive apoptosis after treatment with gefitinib or erlotinib (Shintani et al, 2003;Sordella et al, 2004). EGFR mutations mainly aggregate in two hot spot regions, around codons 746-750 in exon 19 (deletion, 32%) and codon 858 in exon 21 (missense, 38%), while two-thirds of 131 unique mutations have been reported only once and account for only 11% of reported mutations (Gu et al, 2007).…”