Phospholipases cancer, NGF collaborates with Her2 in the activation of an overproliferative phenotype and in pheocromocitoma cells, PC112 NGF downregulates Her2 expression. In addition, Her2 has been shown to heterodymerize with IGF 1R and to contribute to gefitinib resistance. Another possible cause for the gefitinib resistance could be the acquisition of new or secondary EGFR gene mutations affecting the TK domain. It has been shown that gefitinib and erlotinib are able to induce resistance by secondary mutations of the EGFR TK domain. However, although these mutations have been demonstrated to confer drug resistance, we did not consider these EGFR mutations as being responsible for the gefitinib resistance in PCa cells through several functional evidences: i EGFR was able to be activated by its ligands such as EGF, both in untreated or custom peptide synthesis gefitinib resistant cells, and ii 0.5 10 M gefitinib was able to block both basal and EGF mediated p EGFR expression in intact cells. Therefore, this simple functional approach demonstrates that mutations such as T790M, which affect tyrosine activity, if they are present, do not involve threonine 790.
In conclusion, compared with the parental cells, TKI R PC3 PCa cells show i an increment in the basal ERK activation levels, ii an EGF mediated and gefitinib insensitive ERK phosporylation, iii increased levels of Her2/Neu, iv a significant clopidogrel decrement in EGFR expression and activity, v an increased sensitivity to growth inhibition by AG825, an Her2 inhibitor, vi an increased expression of the neutrophine receptors, TrkA and TrkB, without modulation in Trk C and p75 NTR, and vii an increased sensitivity to growth inhibition by CEP701. In addition, MAPK inhibition abolished gefitinib resistance completely, supporting the idea that MAPK activation was associated with gefitinib efficacy and resistance in the PTEN negative PC3 cells. Such data support the importance of the utilisation of chronic exposure models in order to delineate mechanisms of acquired drug resistance as they may reflect the clinical paclitaxel scenario more closely than acute drug challenges. These data have important predictive and therapeutic clinical implications: These results can help to explain the molecular responses in gefitinibresistant prostate tumors and to improve the chemotherapeutic strategies for their clinical treatment.
Moreover, the existence of multiple proliferation signaling pathways in cancer cells could favor the choice of multidrug chemotherapy strategies vs monochemotherapy, with the perspective of higher efficacy paralleled by lower side effects with multiple regimens using lower doses of each drug as compared to monotherapies. A total of 38/40 patients experienced at least one treatment phase related AE. The most frequent drug related AEs were GI disorders in 32/40 patients, nausea in 22/40 patients, diarrhoea in 21/40 patients and vomiting in 21/40 patients, metabolic disorders in 28/40 patients, blood and lymphatic system disorders in 27 patients and general disorders in 26 patients. The most frequent drug related AE was GI toxicity in 32/40 patients including nausea in 22/40 patients, diarrhoea in 21/40 patients and vomiting in 21/40 patients.