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dc.contributor.authorMoreira-Leite, Flavia
dc.contributor.authorHarrison, Luke R
dc.contributor.authorMironov, Alexandr
dc.contributor.authorRoberts, Ruth A
dc.contributor.authorDive, Caroline
dc.date.accessioned2010-08-10T14:49:10Z
dc.date.available2010-08-10T14:49:10Z
dc.date.issued2010-06
dc.identifier.citationInducible EGFR T790M-mediated gefitinib resistance in non-small cell lung cancer cells does not modulate sensitivity to PI103 provoked autophagy. 2010, 5 (6):765-77 J Thorac Oncolen
dc.identifier.issn1556-1380
dc.identifier.pmid20421816
dc.identifier.doi10.1097/JTO.0b013e3181d95d93
dc.identifier.urihttp://hdl.handle.net/10541/109409
dc.description.abstractINTRODUCTION: Non-small cell lung cancer (NSCLC) with certain activating mutations in the epidermal growth factor receptor (EGFR) is sensitive to the small molecule EGFR tyrosine kinase inhibitors gefitinib and erlotinib, although acquired resistance eventually develops. Resistance is often mediated by acquisition of the T790M mutation in the activated EGFR allele. The aim of this study was to investigate in an EGFR tyrosine kinase inhibitor sensitive NSCLC cell line model, the impact of induced EGFR T790M expression on the cell biology and sensitivity to novel therapeutic strategies. METHODS: Doxycycline inducible EGFR T790M-mediated drug resistance was generated in the clinically relevant HCC827 NSCLC cell line. Cell fate, the activities of EGFR and downstream signaling molecules, and the sensitivity to downstream inhibition of EGFR signaling networks were examined in the presence or absence of induced EGFR T790M expression. RESULTS: Inducible EGFR T790M expression generated acquired resistance to EGFR inhibitors in HCC827 cells as expected. However, induced EGFR T790M expression did not affect activity of EGFR downstream signaling pathways or cell proliferation under the conditions tested. Moreover, sensitivity to inhibition of signaling molecules downstream of EGFR was unaffected by induced EGFR T790M. Importantly, HCC827 cells remained sensitive to class I phosphatidyl-inositol-3-kinase and mammalian target of rapamycin inhibition, which provoked pronounced autophagy, without significant apoptosis. CONCLUSIONS: Phosphatidyl-inositol-3-kinase /mammalian target of rapamycin inhibition is a potentially effective therapeutic strategy against NSCLC with acquired resistance to EGFR inhibition. However, the implications of drug-induced autophagy in NSCLC need further exploration.
dc.language.isoenen
dc.subjectNon-Small Cell Lung Canceren
dc.subjectEpidermal Growth Factor Receptoren
dc.subjectT790Men
dc.subjectAutophagyen
dc.subject.meshAntineoplastic Agents
dc.subject.meshCarcinoma, Non-Small-Cell Lung
dc.subject.meshFurans
dc.subject.meshLung Neoplasms
dc.subject.meshPhosphatidylinositol 3-kinases
dc.subject.meshPyridines
dc.subject.meshPyrimidines
dc.subject.meshQuinazolines
dc.titleInducible EGFR T790M-mediated gefitinib resistance in non-small cell lung cancer cells does not modulate sensitivity to PI103 provoked autophagy.en
dc.typeArticleen
dc.contributor.departmentClinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.en
dc.identifier.journalJournal of Thoracic Oncologyen
html.description.abstractINTRODUCTION: Non-small cell lung cancer (NSCLC) with certain activating mutations in the epidermal growth factor receptor (EGFR) is sensitive to the small molecule EGFR tyrosine kinase inhibitors gefitinib and erlotinib, although acquired resistance eventually develops. Resistance is often mediated by acquisition of the T790M mutation in the activated EGFR allele. The aim of this study was to investigate in an EGFR tyrosine kinase inhibitor sensitive NSCLC cell line model, the impact of induced EGFR T790M expression on the cell biology and sensitivity to novel therapeutic strategies. METHODS: Doxycycline inducible EGFR T790M-mediated drug resistance was generated in the clinically relevant HCC827 NSCLC cell line. Cell fate, the activities of EGFR and downstream signaling molecules, and the sensitivity to downstream inhibition of EGFR signaling networks were examined in the presence or absence of induced EGFR T790M expression. RESULTS: Inducible EGFR T790M expression generated acquired resistance to EGFR inhibitors in HCC827 cells as expected. However, induced EGFR T790M expression did not affect activity of EGFR downstream signaling pathways or cell proliferation under the conditions tested. Moreover, sensitivity to inhibition of signaling molecules downstream of EGFR was unaffected by induced EGFR T790M. Importantly, HCC827 cells remained sensitive to class I phosphatidyl-inositol-3-kinase and mammalian target of rapamycin inhibition, which provoked pronounced autophagy, without significant apoptosis. CONCLUSIONS: Phosphatidyl-inositol-3-kinase /mammalian target of rapamycin inhibition is a potentially effective therapeutic strategy against NSCLC with acquired resistance to EGFR inhibition. However, the implications of drug-induced autophagy in NSCLC need further exploration.


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