{"database":"GPMDB","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":23,"searchCount":5},"additional":{"omics_type":["Other"],"submitter":["Koch H, et al."],"instrument_platform":["Instrument"],"disease":["Not Available"],"brenda_tissue":["Not available"],"species":["Homo_sapiens_viruses, Human_female"],"submitter_mail":["heiner.koch@tum.de"],"publication":["25963923"],"model":["http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019968","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019966","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019967","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019959","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019960","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019971","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019961","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019972","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019970","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019975","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019964","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019965","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019976","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019973","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019962","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019974","http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310019963"],"submitter_affiliation":["Technical University of Munich"],"cell_type":["Not available"],"repository":["GPMDB"],"pubmed_abstract":["Tyrosine kinase inhibitors (TKIs) have become an important therapeutic option for treating several forms of cancer. Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR), is in clinical use for treating non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, despite high initial response rates, many patients develop resistance to gefitinib. The molecular mechanisms of TKI resistance often remain unclear. Here, we describe a chemical proteomic approach comprising kinase affinity purification (kinobeads) and quantitative mass spectrometry for the identification of kinase inhibitor resistance mechanisms in cancer cells. We identified the previously described amplification of MET and found EPHA2 to be more than 10-fold overexpressed (p < 0.001) in gefitinib-resistant HCC827 cells suggesting a potential role in developing resistance. siRNA-mediated EPHA2 knock-down or treating cells with the multikinase inhibitor dasatinib restored sensitivity to gefitinib. Of all dasatinib targets, EPHA2 exhibited the most drastic effect (p < 0.001). In addition, EPHA2 knockdown or ephrin-A1 treatment of resistant cells decreased FAK phosphorylation and cell migration. These findings confirm EPHA2 as an actionable drug target, provide a rational basis for drug combination approaches, and indicate that chemical proteomics is broadly applicable for the discovery of kinase inhibitor resistance."],"pubmed_title":["Chemical Proteomics Uncovers EPHA2 as a Mechanism of Acquired Resistance to Small Molecule EGFR Kinase Inhibition."],"pubmed_authors":["Koch Heiner H,Busto M Estela Del Castillo ME,Kramer Karl K,Médard Guillaume G,Kuster Bernhard B,","Koch Heiner H, Busto M Estela Del Castillo ME, Kramer Karl K, Médard Guillaume G, Kuster Bernhard B"],"name_synonyms":["small, receptor tyrosine-protein kinase erbB-1, Transphosphorylases, proto-oncogene c-ErbB-1, underdeveloped, Wa5, TGF-alpha receptor activity, Kinases, ERBB, EGFR, ATP., hypoplasia, Errb1, ERBB1, Myk2, wa-2, mENA, Phosphotransferases, CTRCT6, Sek-2, PIG61, epidermal growth factor receptor activity, reduced, wa2, Errp, ECK, Eck, Erbb, AI552599, resistance, 9030024J15Rik, EGF receptor activity, transforming growth factor-alpha receptor activity, Kinase, tiny, CTPP1, ATP Phosphotransferases, ARCC2, CTPA, HER1, NISBD2, Sek2, AW545284"],"description_synonyms":["HCC-827, C5H11NO2S, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamide, Sprycel, 2-amino-4-(methylsulfanyl)butanoic acid, insensitive, Hgfr, Ass-1, number, 5730555F13Rik, Spectrum Analyses, 27)/f/h27H, presence, (H, Cc1nc(Nc2ncc(s2)C(=O)Nc2c(C)cccc2Cl)cc(n1)N1CCN(CCO)CC1, 354825, Methionine, BMS-354825, HGFR, Roles, AA408052, resistance, Mass, fold, Concepts, 2, Kinase, Analysis, RCCP2, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamine, sensitivity, malignant tumour, Mass Spectroscopy, CTPA, 11-14H, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine, Sek2, InChI=1/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5, Mass Spectrum Analysis, Iressa, 24, 25, 26, COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCOCC1, 28, Analyses, Identification, scatter factor receptor, M, Fatty Acid 22:1 n-9 trans, malignant neoplasia, INSDC_feature:ncRNA, AUTS9, CTRCT6, 27)/f/h27-28H, Sek-2, INSDC_qualifier:siRNA, Brassidic Acid, ASS, Fatty Acid trans 22:1 n-9, 2-amino-4-(methylthio)butanoic acid, dasatinibum, BMS, ECK, Eck, Role Concepts, kinase inhibitor, Sensitivity, InChI=1/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4, C22H24ClFN4O3, ATP Phosphotransferases, RG7MT1, metionina, HCC827, Racemethionine, downregulation of kinase activity, ATP, Cancer, BMS Dasatinib, data, proto-oncogene c-Met, Trans docos-13-enoic Acid, 12-13, Malignant Neoplasm, small interfering RNA, DL-Methionine, InChIKey=XGALLCVXEZPNRQ-LELJVTLKCM, 2-Amino-4-(methylthio)butyric acid, 9130215G10Rik, Spectrum Analysis, Phosphotransferases, Cell, ZD1839, BMS354825, Concept, Spectroscopy, count in organism, Role Concept, count, C22H26ClN7O2S, 31H, down regulation of kinase activity, inhibition of kinase activity, 32)(H, 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, Role, Methionin, methionine, Hmet, BMS 354825, ARCC2, Mass Spectrum Analyses, Met, MET, HGF/SF receptor, HGF receptor, N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1, Mass Spectrum, Transphosphorylases, 1-2H3, resistant, Kinases, N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, tyrosine-protein kinase Met, n-9 trans, ZD1839., Spectrometry, Specificity, Identifications (Psychology), (18F)-N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, Cancers, Myk2, ZD 1839, hCMT1c, c-Met, down-regulation of kinase activity, malignant tumor, 1H3, 5-10H2, Specificity and Sensitivity, alpha-amino-gamma-methylmercaptobutyric acid, 3-thiazole-5-carboxamide, InChIKey=ZBNZXTGUTAYRHI-VEORKLDJCJ, quantitative, CTPP1, 6-11H2, 5730455C01Rik, Proteomes, C22:1, SF receptor, presence or absence in organism, AW545284"],"pubmed_title_synonyms":["small, receptor tyrosine-protein kinase erbB-1, Transphosphorylases, proto-oncogene c-ErbB-1, underdeveloped, Wa5, TGF-alpha receptor activity, Kinases, ERBB, EGFR, ATP., hypoplasia, Errb1, ERBB1, Myk2, wa-2, mENA, Phosphotransferases, CTRCT6, Sek-2, PIG61, epidermal growth factor receptor activity, reduced, wa2, Errp, ECK, Eck, Erbb, AI552599, resistance, 9030024J15Rik, EGF receptor activity, transforming growth factor-alpha receptor activity, Kinase, tiny, CTPP1, ATP Phosphotransferases, ARCC2, CTPA, HER1, NISBD2, Sek2, AW545284"],"pubmed_abstract_synonyms":["Sprycel, insensitive, Hgfr, Ass-1, Non-Small Cell Lung Cancer, 5730555F13Rik, Errb1, 27)/f/h27H, phosphorylation, PIG61, Mutations, Cc1nc(Nc2ncc(s2)C(=O)Nc2c(C)cccc2Cl)cc(n1)N1CCN(CCO)CC1, Lung Carcinomas, Methionine, HGFR, Roles, AI552599, responsivity, AA408052, Non-Small-Cell Lung Carcinoma, symptoms, fold, Concepts, 2, Kinase, Analysis, Non-Small Cell Lung Carcinoma, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamine, present in fewer numbers in organism, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine, CTPA, InChI=1/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5, Mass Spectrum Analysis, treatment, 24, 25, 26, COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCOCC1, 28, Analyses, Identification, M, tyrosine kinase inhibitors, Non-Small Cell Lung, Non Small Cell Lung Carcinoma, INSDC_feature:ncRNA, INSDC_qualifier:siRNA, ASS, decreased, dasatinibum, RPTK Ligand, medicine, Role Concepts, disease management, 9030024J15Rik, InChI=1/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4, ATP Phosphotransferases, RG7MT1, HCC827, Racemethionine, EPLG1, downregulation of kinase activity, NISBD2, ATP, BMS Dasatinib, close to, screening, Carcinoma, Fadk, proto-oncogene c-Met, Ligand, Trans docos-13-enoic Acid, Wa5, small interfering RNA, InChIKey=XGALLCVXEZPNRQ-LELJVTLKCM, Eck Ligand, 2-Amino-4-(methylthio)butyric acid, 9130215G10Rik, Spectrum Analysis, Spectroscopy, FADK, Role Concept, count, wa2, inhibition of kinase activity, 32)(H, 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, Role, Methionin, concluding remarks, methionine, Hmet, BMS 354825, Carcinomas, HGF/SF receptor, HGF receptor, Transphosphorylases, resistance., resistant, EGFR, conclusion, Spectrometry, signs, Identifications (Psychology), ZD 1839, hCMT1c, c-Met, 1H3, Non Small Cell Lung, 5-10H2, Endothelium Secreted Protein B61, summary, Patient, Specificity and Sensitivity, FAK, InChIKey=ZBNZXTGUTAYRHI-VEORKLDJCJ, 6-11H2, AW545284, receptor tyrosine-protein kinase erbB-1, HCC-827, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamide, C5H11NO2S, 2-amino-4-(methylsulfanyl)butanoic acid, proto-oncogene c-ErbB-1, LERK 1 Protein, number, Non-Small-Cell Lung, Spectrum Analyses, mENA, presence, (H, 354825, BMS-354825, conclusions, reduced, subnumerary, resistance, Endothelium, Mass, EGF receptor activity, mKIAA4203, RCCP2, sensitivity, malignant tumour, NONSMALL CELL LUNG CARCINOMA, 11-14H, Mass Spectroscopy, Sek2, Iressa, reactivity, scatter factor receptor, Fatty Acid 22:1 n-9 trans, malignant neoplasia, decreased number, Lung Carcinoma, AUTS9, CTRCT6, 27)/f/h27-28H, Sek-2, Brassidic Acid, FAK1, NSCLC, Epl1 Protein, drugs, Fatty Acid trans 22:1 n-9, 2-amino-4-(methylthio)butanoic acid, BMS, Clients, ECK, Eck, kinase inhibitor, Sensitivity, C22H24ClFN4O3, metionina, Non-Small-Cell Lung Carcinomas, Cancer, use, 12-13, findings, Malignant Neoplasm, pp125FAK, DL-Methionine, TGF-alpha receptor activity, ERBB, drug, Phosphorylations, Client, Phosphotransferases, Cell, p125FAK, ZD1839, Non-small cell lung cancer (disorder), BMS354825, Concept, near to, count in organism, epidermal growth factor receptor activity, FRNK, C22H26ClN7O2S, 31H, down regulation of kinase activity, protein tyrosine kinase inhibitor, Eck RPTK Ligand, ARCC2, Mass Spectrum Analyses, Met, MET, N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1, Mass Spectrum, 1-2H3, Kinases, N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, tyrosine-protein kinase Met, n-9 trans, Specificity, (18F)-N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, ERBB1, Cancers, Myk2, wa-2, down-regulation of kinase activity, malignant tumor, LERK-1 Protein, PPP1R71, B61 Secreted Protein, Errp, approaches, Erbb, vicinity of, alpha-amino-gamma-methylmercaptobutyric acid, 3-thiazole-5-carboxamide, transforming growth factor-alpha receptor activity, response, quantitative, Ephrin A1, CTPP1, 5730455C01Rik, HER1, C22:1, SF receptor, Non-Small-Cell, presence or absence in 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archive~1","varsite~0"],"reanalysis_count":["0"],"submitter_keywords":["Resource Reanalysis"],"citation_count_scaled":["0.0"],"reanalysis_count_scaled":["0.0"],"view_count_scaled":["0.007094386181369525"],"download_count_scaled":["0.0"],"normalized_connections":["1.0"],"additional_accession":[]},"is_claimable":false,"name":"Chemical proteomics uncovers EPHA2 as a mechanism of acquired resistance to small molecule EGFR kinase inhibition.","description":"Data from ProteomeXchange, PXD ID: PXD001333. File: 000249_D01_P001442_B00_A00_R1.mzml. Published as part of J Proteome Res. 2015 May 12  . From the Abstract: {{i}} ... Here, we describe a chemical proteomic approach comprising kinase affinity purification (kinobeads) and quantitative mass spectrometry for the identification of kinase inhibitor resistance mechanisms in cancer cells. We identified the previously described amplification of MET and found EPHA2 to be more than 10-fold overexpressed (p<0.001) in gefitinib resistant HCC827 cells suggesting a potential role in developing resistance. siRNA mediated EPHA2 knock-down or treating cells with the multi-kinase inhibitor dasatinib restored sensitivity to gefitinib ... {{/i}}","dates":{"submission":"2015-05-20"},"accession":"GPM32310019962","cross_references":{"pubmed":["25963923"],"Pride":["PXD001333"],"pride":[],"Pride Archive":["PXD001333"]}}