A majority of gefitinib (IRESSA)-responsive tumours in non-small cell lung cancer have been found to carry mutations in ErbB1. Previously, it has been observed that internalisation-deficient ErbB1 receptors are strong drivers of oncogenesis. Using a computational model of ErbB1 trafficking and signalling, it is found that a deficiency in ErbB1 internalisation is sufficient to explain the observed signalling phenotype of these gefitinib-responsive ErbB1 mutants in lung cancer cell lines. Experimental tests confirm that gefitinib-sensitive cell lines with and without ErbB1 mutations exhibit markedly slower internalisation rates than gefitinib-insensitive cell lines. Moreover, the computational model demonstrates that reduced ErbB1 internalisation rates are mechanistically linked to upregulated AKT signalling. Experimentally it is confirmed that impaired internalisation of ErbB1 is associated with increased AKT activity, which can be blocked by gefitinib. On the basis of these experimental and computational results, it is surmised that gefitinib sensitivity is a marker of a reliance on AKT signalling for cell survival that may be brought about by impaired ErbB1 internalisation.
The Warburg theory of carcinogenesis is reexamined in the light of recent information, and objections are discussed. We conclude that these objections are not valid in view of the present data. Intercellular communication in normal cells and its lack in tumors is discussed. A model of carcinogenesis in which cell oscillations are related to intercellular communication is shown to have support. Several different pathways to cancer are shown ro result. Therapeutic implications, including activated oxygen by means of negative ions and electromagnetic excitation as therapy, are suggested. A possible role of antioxidant vitamins in retarding cancer is considered. A unified outlook of several levels of carcinogenesis is now possible and lines of further research are suggested.
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