Enhancement of tumor radioresponse by combined treatment with gefitinib (Iressa, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DNA damage repair and cell growth in oral cancer

Abstract

Molecular blockade of EGFR with either an EGFR MAb or an EGFR TKI enhances the radiosensitivity of human SCCs.In the present study, we investigated whether treatment with the EGFR TKI gefitinib (Iressa, ZD1839) improves the response to radiotherapy in the OSCC cell lines HSC2 and HSC3. We examined potential mechanisms that may contribute to the enhanced radiation response induced by gefitinib. Growth inhibition was observed in vitro with radiation or gefitinib. A cooperative antiproliferative effect was obtained when cancer cells were treated with radiation followed by gefitinib. Cells treated with a combination of radiation and gefitinib arrested in G 1 and G 2 -M phases, with a decrease in the S-phase population. While radiation alone did not significantly affect MEK1/2 and p38 MAPK autophosphorylation, the combination of gefitinib and radiation completely inhibited the downstream signaling of EGFR. Results from DNA damage repair analysis in cultured OSCC cells demonstrated that gefitinib had a strong inhibitory effect on DNAPKc pathways after radiation. Tumor xenograft studies demonstrated that the combination of gefitinib and radiation caused growth inhibition and tumor regression of well-established OSCC tumors in athymic mice; tumor volume was reduced from 1,008.2 to 231.4 mm 3 in HSC2 cells (p < 0.01) and from 284.2 to 12.4 mm 3 in HSC3 cells (p < 0.01). Immunohistochemical analysis of OSCC xenografts revealed that gefitinib caused a striking decrease in tumor cell proliferation when combined with radiotherapy. Overall, we conclude that gefitinib enhances tumor radioresponse by multiple mechanisms that may involve antiproliferative growth inhibition and effects on DNA repair after exposure to radiation.

Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

“…Finally, just recently, Bonner et al (54) showed in a clinical study the clear advantage of combined C225 and radiotherapy over radiotherapy alone for head and neck cancer patients. Similar findings on enhanced radiation sensitivity have been reported for tyrosine kinase inhibitors that target the kinase activity of EGFR (55). Nevertheless, especially for tyrosine kinase inhibitors, a big heterogeneity for enhanced radiation sensitivity seems to be obvious and even dependent on concomitant mutations as reported by us recently (30).…”

Targeting fibroblast growth factor receptor 3 enhances radiosensitivity in human squamous cancer cells

“…Although previous studies have reported an association between enhanced radiosensitivity in oral SCC and certain gene expression (Shintani et al, 2003;Ishigami et al, 2007), to the best of our knowledge, the current report is the first on the use of the combination of an FGFR3 inhibitor and radiation in vitro and in vivo. Finally, the current data supported the idea that combination therapy with radiation and an FGFR3 inhibitor increases the therapeutic efficacy of radiation in human cancers including SCCs.…”

Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2

“…EGFR-targeted therapies, including gefitinib (Iressa ® ; AstraZeneca, London, UK) (26,(28)(29)(30) and cetuximab (Erbitux ® ; Eli Lilly and Company, Indianapolis, IN, USA) (31,32), have been studied extensively as potential methods of blocking the cancer-promoting functions of EGFR in OSCC. However, although it has been reported that EGFR inhibitors are initially beneficial for the treatment of cancer, resistance to the inhibitors eventually develops (21,33).…”