EGFR tyrosine kinase inhibitor "gefitinib (Iressa)" for cancer therapy.

Abstract

Many malignant tumors including non-small cell lung cancer (NSCLC) express or over-express EGFR that have shown correlations with rapid growth, metastases, resistance to conventional chemotherapy or radiotherapy, and poor prognosis. Gefitinib is a potent and selective inhibitor of EGFR tyrosine kinase (EGFRTK). Gefitinib specifically inhibited EGF-stimulated cell proliferation in vitro and it also exhibited a broad anti-tumor spectrum against NSCLC, prostate, colorectal, and ovarian cancers in vivo. Gefitinib showed dose-dependent and reversible reduction of c-fos mRNA level and decreased Ki67 significantly in tumors in vivo. In in vitro studies, gefitinib arrested the cell cycle at G1 phase by inducing intrinsic cyclin-dependent kinase (cdk) inhibitors and following inhibition of cdk2. Apoptosis was also seen in gefitinib-treated tumor cells and skin biopsy samples from clinical study. Gefitinib inhibited VEGF production in tumor cells through inhibition of EGFR signaling, leading to suppression of angiogenesis. In clinical studies, gefitinib demonstrated therapeutic benefit in patients who failed conventional chemotherapy. No correlation has been established between the anti-tumor activity of gefitinib and EGFR expression level, whilst sensitivity factors to gefitinib are yet to be elucidated. Identification of sensitivity factors will be a key for effective use of EGFRTK inhibitors including gefitinib for cancer treatment.

Advances in anti-VEGF and anti-EGFR therapy for advanced non-small cell lung cancer

“…Both selectively inhibit EGFR tyrosine kinase, reducing autophosphorylation and thereby disrupting EGFR signaling [29,30]. This leads to inhibition of cell proliferation, blockade of cell cycle progression and stimulation of apoptosis, with consequent inhibition of tumor growth.…”

Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer

“…Likewise, VEGF and VEGF receptor kinases are also good candidates for anti-angiogenic treatment strategy. In fact, it was shown that Gefitinib (ZD 1839), a potent and selective inhibitor of EGFR tyrosine kinase, caused inhibition of VEGF production in tumor cells through the inhibition of EGFR signaling, leading to a suppression of angiogenesis (42). Angiogenesis is a complex process regulated by a great variety of stimulators and inhibitors and of these, VEGF-A is considered as the most potent pro-angiogenic factor.…”

C-fos Assessment as a Marker of Anti–Epidermal Growth Factor Receptor Effect

“…C-fos expression is regulated at multiple levels by intracellular signaling events, which makes it a useful marker to identify and characterize factors that affect cancer cell growth. C-fos is a robust marker of proliferation and it has been used as a distal marker to assess EGFR activation (8) and anti-EGFR therapy (9). In this article, we tested whether variations in c-fos expression corresponded to EGFR in vitro and in vivo inhibition and whether c-fos mRNA could be developed as a biomarker to predict sensitivity to EGFR blockade using an ex vivo approach.…”