A hypothetical model of how drug sensitivity to gefitinib is controlled in HER expressing NSCLC cells.In gefitinibresistant cell lines with no significant expression of EGFR, EGFR is not a survival factor for these cells.Cell proliferation and apoptosis are Revefenacin expected to be driven by other growth factor receptors that might not be targets for gefitinib.Therefore, cell survival and death, both of which are dependent on HERHER signaling, are highly susceptible to gefitinib.In conclusion a NSCLC cell line, LK, has no apparent expression of EGFR and HER, but expresses HER moderately, suggesting that HER does not seem to act as survival factors in LK cells.Cell proliferation and apoptosis in LK cells are expected to be driven by other growth factor receptors that are not targets for gefitinib. Overexpression of EGFR in LK cells resulted in no altered drug sensitivity to gefitinib. Cell survival and death, which are dependent on HERHER signaling, are then expected to be highly responsive to gefitinib treatment.The costs of publication of this article were defrayed in part by the payment of page charges.Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD, an inhibitor of EGFR tyrosine kinase.Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from cancerres.aacrjournals.org on April. American Association for Cancer Research. We evaluated the efficacy of TAE against NSCLC cell lines in vitro and in vivo.EMLALK was detected more frequently in NSCLC patients who were never or light. In another EMLALK cell line, DFCI, TAE was ineffective due to coactivation of epidermal growth factor receptor and ERBB.Conclusions: EMLALK is found in the minority of NSCLC.ALK kinase inhibitors alone or in combination may never theless be clinically effective treatments for NSCLC patients whose tumors contain EMLALK. The costs of publication of this article were defrayed in part by the payment of page charges.Inhibitors of ALK kinase have been developed and examined in preclinical models.Proofofconcept studies using short hairpin RNA knockdown of ALK in NPMALK containing models led to growth inhibition and apoptosis and suggested that ALK inhibition may be a potentially effective therapeutic strategy. This has lead to the development and testing of smallmolecule inhibitors of ALK.Initial studies have been done using less potent ALK inhibitors such as WHIP. Subsequently, more potent and specific ALK inhibitors such as diaminopyrimidines or aminopyrimidines have been developed including TAE and PF. Both of these inhibitors have good bioavailability and inhibit ALK kinase activity and growth of NPMALK positive lymphoma cells in the low nanomolar range. The PC, A, H, and H cells were cultured in RPMI supplemented with fetal bovine serum, unitsmL streptomycin, and mmolL sodium pyruvate.The DFCI cells were cultured in ACL medium supplemented with fetal bovine serum, unitsmL streptomycin, and mmolL sodium pyruvate.NSCLC tumors were collected from surgical resections from patients with stages I to IIII NSCLC when sufficient material for RNA extraction was available.One or two pieces from the periphery of the tumor masses, avoiding necrotic regions, were immediately frozen at jC until retrieved.Only frozen tumor tissues from adenocarcinoma or squamous cell carcinoma were included.

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