HSP addition, a subset of human tumors is driven by the overexpression and overactivity of the EGFR family proteins. Also, many solid tumours also demonstrate an elevated expression of the corresponding EGFR ligands, EGF and the transforming growth factor, suggesting that the receptor can be activated in an autocrine manner. In breast cancer, for example, EGFR overexpression has been associated with oestrogen receptor negative disease and hence with poor prognosis, while in vitro studies have also implicated EGFR in the mediation of acquired resistance to anti oestrogen therapy. In PCa 80% of cases display EGFR or Her2 gene overexpression and it has been shown that ErbB1 expression is strongly associated with hormone refractory status and this suggests that drugs targeted toward ErbB signaling could be of therapeutic relevance in the management of advanced chondroitin prostatic carcinoma. Signal transduction through the ErbB receptor family involves the Raf MEK MAP kinase and the PI3 kinase/Akt signaling pathways.
These pathways are often activated simultaneously with conflicting responses such as apoptosis, proliferation, growth arrest, differentiation,and senescence, depending on the cell type and the duration and strength of the stimulus. Gefitinib is an oral glycyrrhetin nonpeptidic anilinoquinazolone compound that inhibits the TRK activity of the EGFR Erb B1. Fabian et al reported that gefitinib binds 16 kinases plus EGFR, the corresponding Kd for EGFR being 1000 fold higher, whereas for GAK the corresponding Kd for EGFR was about 10 fold higher. However, gefitinib can be used to specifically inhibit EGFR at doses lower than 10 M. Gefitinib inhibits the growth of cell lines that express high levels of EGFR and induces the complete regression of well established xenografts. In addition, we have demonstrated that gefitinib is able to reduce the invasiveness and metastasis of PCa cells. Gefitinib has been included in clinical trials in cancer patients, and antitumor activity has been demonstrated against several human cancers, such as recurrent or metastatic squamous head and neck cell carcinoma, non small cell lung cancer and prostate cancer. However, the celecoxib clinical data have already demonstrated that not all patients respond to the inhibitor, indicating the existence of an intrinsic or de novo resistance to the drug.
However, although in vitro studies have indicated a potential higher effectiveness of gefitinib in advanced PCa as a single therapeutic agent or in combination with chemotherapeutics, the drug has shown minimal single agent activity in the clinically advanced phases of the disease. The acquisition of resistance to gefitinib has also been demonstrated in vitro, with the primary establishment of different gefitinib/erlotinib resistant cell lines due to EGFR secondary mutations in the tyrosine kinase inhibitor domain in non small cell lung carcinoma and oesophageal cancer as well as in the activation of alternative signaling pathways in breast cancer and PCa. In our study, we generated a model for the acquired resistance to gefitinib using an androgen independent, EGFRpositive, and phosphatase and tensin homologue deleted from chromosome 10 negative PC3 cell line, with a slow sensitivity to gefitinib, in which an increased Her2 and TrkA mediated mitogen activated.