Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors

摘要: We have examined the possible mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibitors in tumor cells with variable levels EGFR. ZD1839 (Iressa) is a small-molecular-weight, ATP-mimetic that specifically inhibits EGFR tyrosine kinase. A431 cell was markedly inhibited by (IC(50)< or =0.1 microM) whereas MDA-468 were relatively resistant (IC(50)2 microM). Low doses delayed cycle progression and induced apoptosis but not cells. In both lines, 0.1 microM eliminated phosphorylation. However, basal activity phosphatidylinositol-3 kinase (PI3 K) target Akt cells, implying their independent signals. express PTEN/MMAC1/TEP, phosphatase can dephosphorylate position D3 phosphatidylinositol-3,4,5 trisphosphate, site recruits plecstrin-homology domain membrane. On contrary, lack tensin homolog (PTEN), potentially setting at high threshold unresponsive inhibition alone. Therefore, we reintroduced (PTEN) retroviral infection MDA-468/PTEN vector controls, treatment P-Akt levels, relocalization Forkhead FKHRL1 nucleus, increased FKHRL1-dependent transcriptional activity. greater degree delay PTEN-reconstituted than control These data suggest loss PTEN, permitting level inputs, temporally dissociate inhibitors. Thus, EGFR-expressing concomitant amplification(s) PI3K-Akt signaling, combined blockade should be considered as therapeutic approach.