It seems likely that PI3K Akt pathway is not mutated during collection of drug resistant cell lines. All through choice of drug resistant Foretinib VEGFR inhibitor cell lines from PC9, HER3 and HER2 hence seem to activate PI3K/Akt pathway in erlotinibresistant cells, and this HER2/HER3 pushed Akt activation pathway may play a pivotal position in acquired resistance to erlotinib in PC9/ER1 cells. HER2 and her3 in its close experience of wild type EGFR might also in part contain acquirement of drug resistance. A relevant research has previously demonstrated that HER2/HER3 driven signaling pathway limits sensitivity to EGFR targeted drugs in cancer cells. On the other hand, exogenous transfection of activated mutant EGFR cDNA partly renewed drug sensitivity to erlotinib in 18/ER1 7 cells and knock-down of HER3 or HER2 also sensitized cells to erlotinib by inhibiting phosphorylation of Akt. Similar mechanism as in PC9 might be involved in acquirement of drug resistance to erlotinib in 18. But, more accurate research should be further required to comprehend the main mechanism for drug resistance in 18. During acquirement of drug resistance to EGFR precise drugs, activation by by-pass elements and genomic Latin extispicium alternation affecting up stream or down stream effectors will also be involved. Along with PI3K/Akt service independent of activated mutant EGFR in erlotinib and/or gefitinib resistant cell lines, we also examined whether other mechanisms could play any part in acquirement of drug resistance. Alternative activation of c Met and IGF1R abrogate the close association of EGFR with cell survival, accompanied by tumor growth that’s independent of EGFR. In particular, overexpression of IGF1R has been around EGFR TKI resistant cell lines based on 18. Our erlotinib and gefitnib resistant cell lines present similar sensitivity to the IGF1RTKI, natural product library, and c Met TKI as their parental cell lines. Moreover, from RTK selection, service status of PDGFR, AXL, h Met, and IGF1R was not triggered in immune cells lines as compared using their parental version, suggesting that these kinase pathways aren’t likely involved. Furthermore, DNA sequence analysis showed no acquisition of a representative extra mutation of drug resistance in lung cancer cells, T790M mutation. Phosphorylation of Akt was found to be susceptible to PIK3CA knock-down, and also PI3K inhibitors, wortmannin and LY294002 in PC9/ER1. Additionally, neither causing mutation in PIK3CA nor PTEN mutation was seen. Eleven NSCLC patients with adenocarcinomas harbored initiating EGFR versions, including L858R and E746 A750del, and became refractory to treatment with gefitinib. In these individuals, pleural dissemination of cancer cells was observed in the cerebrospinal fluid and pleural cavity after treatment. Out-of 11patients, 3 cases showed loss in activating mutant EGFR after recurrence. However, 1 out-of 3 cases harbored wild type EGFR with T790M mutation.