{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/79313"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/79313","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Dissecting the Role of Epithelial Mesenchymal Transition and 1,25(OH)2D3 Activity in EGFR-Mutant Tyrosine Kinase Inhibitor-Resistant Lung Cancer","abstract":"Ph.D.","abstract_html":"Ph.D.","abstract_has_math":false,"creators":["Shaurova, Tatiana; 0000-0002-5596-4179"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Hershberger, Pamela","Roswell Park"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-04-04T15:57:16Z","date_published":"2019-04-04T15:57:16Z","updated_at":"2026-07-27T19:05:14Z","subjects":["cellular","molecular","bioinformatics","cancer sciences"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/79313","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Hershberger, Pamela","Roswell Park"]},{"key":"dc:creator","label":"Author","values":["Shaurova, Tatiana; 0000-0002-5596-4179"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019-04-04T15:57:16Z","2019","2019-01-02 14:42:15"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Text","Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["cellular","molecular","bioinformatics","cancer sciences"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/79313"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Ph.D.","The body of work presented here describes three in vitro models of EGFR-mutant TKI-resistant NSCLC derived from EGFR TKI-sensitive cell lines in our laboratory. Two cell lines, H1975-OR and SH416-ER, underwent EMT. H1975-OR lack any evidence of kinase switch as a part of the resistance mechanism. To determine the causes of EMT and EGFR TKI resistance in this cell line, RNA sequencing followed by gene set enrichment analysis (GSEA) were performed. In addition to EMT, we detected prominent cell cycle suppression with downregulation of the E2F family of transcription factors and dysregulation of chromatin remodeling pathways. Specifically, downregulation of polycomb repressive complex 2 (PRC2) methyltransferase activity was detected in H1975-OR and SH416-ER cells but not in PC9-ER cells, an EGFR TKI-resistant subline that maintained epithelial phenotype. By utilizing GSK126, a specific inhibitor of EZH2, the catalytic unit of PRC2, we demonstrated that signals originating from downregulation of PRC2 methyltransferase activity are linked to transition towards more mesenchymal phenotype in EGFR-mutant NSCLC. This effect was not cell line specific, as both H1975 and SH416 cells treated with GSK126 increased expression of ZEB2 and decreased EPCAM, well characterized mesenchymal and epithelial markers, respectively. Furthermore, both cell lines treated with GSK126 developed more invasive phenotype, functionally confirming the onset of EMT. This phenotypic switch, however, was not associated with loss of sensitivity to EGFR TKIs. Furthermore, sh_CDH1-driven depletion of E-cadherin in H1975 cells produced similar results. Cells exhibited reduced levels of E-cadherin and increased migration without change in sensitivity to EGFR TKI. Therefore, our results suggest that transition towards more mesenchymal phenotype alone is not sufficient to drive EGFR TKI resistance in our models of EGFR-mutant NSCLC."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Dissecting the Role of Epithelial Mesenchymal Transition and 1,25(OH)2D3 Activity in EGFR-Mutant Tyrosine Kinase Inhibitor-Resistant Lung Cancer"]}]}],"canonical_facts":{"dc:contributor":["Hershberger, Pamela","Roswell Park"],"dc:creator":["Shaurova, Tatiana; 0000-0002-5596-4179"],"dc:date":["2019-04-04T15:57:16Z","2019","2019-01-02 14:42:15"],"dc:description":["Ph.D.","The body of work presented here describes three in vitro models of EGFR-mutant TKI-resistant NSCLC derived from EGFR TKI-sensitive cell lines in our laboratory. Two cell lines, H1975-OR and SH416-ER, underwent EMT. H1975-OR lack any evidence of kinase switch as a part of the resistance mechanism. To determine the causes of EMT and EGFR TKI resistance in this cell line, RNA sequencing followed by gene set enrichment analysis (GSEA) were performed. In addition to EMT, we detected prominent cell cycle suppression with downregulation of the E2F family of transcription factors and dysregulation of chromatin remodeling pathways. Specifically, downregulation of polycomb repressive complex 2 (PRC2) methyltransferase activity was detected in H1975-OR and SH416-ER cells but not in PC9-ER cells, an EGFR TKI-resistant subline that maintained epithelial phenotype. By utilizing GSK126, a specific inhibitor of EZH2, the catalytic unit of PRC2, we demonstrated that signals originating from downregulation of PRC2 methyltransferase activity are linked to transition towards more mesenchymal phenotype in EGFR-mutant NSCLC. This effect was not cell line specific, as both H1975 and SH416 cells treated with GSK126 increased expression of ZEB2 and decreased EPCAM, well characterized mesenchymal and epithelial markers, respectively. Furthermore, both cell lines treated with GSK126 developed more invasive phenotype, functionally confirming the onset of EMT. This phenotypic switch, however, was not associated with loss of sensitivity to EGFR TKIs. Furthermore, sh_CDH1-driven depletion of E-cadherin in H1975 cells produced similar results. Cells exhibited reduced levels of E-cadherin and increased migration without change in sensitivity to EGFR TKI. Therefore, our results suggest that transition towards more mesenchymal phenotype alone is not sufficient to drive EGFR TKI resistance in our models of EGFR-mutant NSCLC."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/79313"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["cellular","molecular","bioinformatics","cancer sciences"],"dc:title":["Dissecting the Role of Epithelial Mesenchymal Transition and 1,25(OH)2D3 Activity in EGFR-Mutant Tyrosine Kinase Inhibitor-Resistant Lung Cancer"],"dc:type":["Text","Dissertation"]},"updated_at":"2026-07-27T19:05:14Z"}