EGA00190GenomicsAB 5500 Genetic AnalyzerOtherhttps://ega-archive.org/studies/EGAS00001001102EGAEGA study EGAS00001001102EGFR Mutant SCLC transformed exome seqEGArestrictedTyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.Niederst Matthew J MJ, Sequist Lecia V LV, Poirier John T JT, Mermel Craig H CH, Lockerman Elizabeth L EL, Garcia Angel R AR, Katayama Ryohei R, Costa Carlotta C, Ross Kenneth N KN, Moran Teresa T, Howe Emily E, Fulton Linnea E LE, Mulvey Hillary E HE, Bernardo Lindsay A LA, Mohamoud Farhiya F, Miyoshi Norikatsu N, VanderLaan Paul A PA, Costa Daniel B DB, Jänne Pasi A PA, Borger Darrell R DR, Ramaswamy Sridhar S, Shioda Toshi T, Iafrate Anthony J AJ, Getz Gad G, Rudin Charles M CM, Mino-Kenudson Mari M, Engelman Jeffrey A JADER/faint little ball, Drob-1/Debcl/dBORG-1, Networks, lung neoplasms, poorly differentiated endocrine neoplasm, insensitive, Kinship, determination, oat cell lung carcinoma, Elp-B1, der, Elp-1, Errb1, Tumor, PPP1R50, ADNOS, Drob-1/Debcl/dBorg-1/dBok, PIG61, Mutations, small cell cancer of the lung, dmTAF[[II]]230, relapse, borg1/debcl, uninterrupted, Kinase Inhibitors, Drob-1/Debcl/dBorg-1/DBok, parenchyma of lung, Tyrosine Kinase Inhibitor, epidermal growth factor-activated receptor activity, oat cell carcinoma of the lung, AI552599, debok, adenocarcinomas, Line, symptoms, 1, Life Cycle, Inhibitors, d-egf-r, present in fewer numbers in organism, ABT-263, Family Life Cycle, average, increased, tumor of lung, Gene Expressions, Kinship Network, TFIID TAF250, Biopsies, cel, Iprit, tyrosine kinase inhibitors, hypoplasia, small cell neuroendocrine carcinoma of the lung, dBrog-1, oat cell carcinoma of lung, flb, CG33134, debc1, genetic, allergic reaction, decreased, CG14648, tumor of the lung, 1-chloro-2-[(2-chloroethyl)sulfanyl]ethane, mustard gas, Therapies, 9030024J15Rik, D-EGFR, associated, Family Life Cycles, tyrphostin, NISBD2, DER1, Tyrosine Protein Kinase Inhibitors, Therapy, neoplasm of lung, dBORG-1/DROB-1/DEBCL/dBOK, screening, dTAF[[II]]230, Growl, pulmo, Elp, Wa5, l(2)09261, lung tumor, DEgfr, BG1, familial, TAF200, lung parenchyma, dBok, dBOK, Normalcy, TAFII-250, bis(2-chloroethyl) sulfide, TAF250/230, somatic, small cell carcinoma of lung, TKI Tyrosine Kinase Inhibitors, CG10079, Tyrosine, non-small cell lung cancer, bcl-2, torpedo/egfr, TAFII250, bis(2-chloroethyl)sulfane, dBorg01, wa2, DmelCG33134, tyrphostins, Filiation, non-small cell lung carcinoma (disease), neoplasms, Lines, Bcl-2, egfr, adenocarcinoma NOS (morphologic abnormality), DBok, absence, HD-33, El, Debcl/dBorg-1/dBok/Drob-1, resistant, EGFR, DER/EGFR, EGfr, EgfR, dEgfr, signs, DER flb, Torpedo/Egfr, CG17603, Dbok, TAF[[II]], Treatments, Tyrosine Kinase, Degfr, CG12397, ABT 263, non-small cell carcinoma of lung, Life Cycles, Health, Drob-1, Taf250, pulmonary, Patient, Debcl/Drob-1/dBorg-1/dBok, SR3-5, DEGFR, l(2)57DEFa, l(2)05351, hypersensitivity reaction disease, dEGFR, lung tumour, inherited genetic, dbok, lung neoplasm, DmHD-33, TAF230, accessory, receptor tyrosine-protein kinase erbB-1, d230, D-Egf, Family Member, proto-oncogene c-ErbB-1, dBorg-1, non-small cell lung carcinoma, C-erb, small cell lung carcinoma, xBcl-2, TKI inhibitor, dbok/debcl, mor1, Gene, dTAFII250, Network, non-small cell carcinoma of the lung, Yperite, mENA, EK2-6, EfW1, small cell lung cancer, supernumerary, non-small cell cancer of the lung, reduced, dmTAF1, Taf230, subnumerary, sensitive, debcl/Borg1, c-erbB, EGFr, Egfr, lung, EGF receptor activity, torpedo/Egfr, TOP, Egf-r, NSCLC - non-small cell lung cancer, Mustard gas, tiny, 1'-thiobis(2-chloroethane), neoplasm, neoplasm of the lung, sensitivity, TAF250, Normalities, Taf200, EGF-R, TKI inhibitors, dTAF[[II]]250, Research, cell, absent from organism, anon-WO0118547.126, Bok(Debcl), lung small cell neuroendocrine carcinoma, dBorg1, top, Taf1p, Torpedo/DER, growl, decreased number, drob-1, Expressions, oat cell carcinoma (morphologic abnormality), top/flb, bis(2-chloroethyl) sulphide, Lost, dTAF250, NSCLC, oat cell carcinoma., protein tyrosine kinase inhibitors, adenocarcinoma, l(2)57EFa, Clients, lung small cell carcinoma, AW986256, lung oat cell carcinoma, l(2)57Ea, DmelCG14648, hypersensitivity reaction, Expression, xbcl2, Kinship Networks, dborg1, TAF, constitutitional genetic, Family, lung neoplasm (disease), tumour of lung, sulfur mustard, oat cell carcinoma, small, Elp-B1RB1, small-cell cancer of lung, TAF[[II]]250, findings, ABT263, Family Research, 1-chloro-2-[(2-chloroethyl)thio]ethane, TGF-alpha receptor activity, ERBB, dEGFR1, malignant, Cell Lines, l(3)84Ab, BG:DS00004.13, Client, Cell, nev, BOK, Bok, dTAF230, no subtype (morphologic abnormality), small cell carcinoma of the lung, small cell neuroendocrine carcinoma of lung, Family Members, Debcl/dBorg-1/dRob-1, epidermal growth factor receptor activity, DmelCG10079, p230, chemical analysis, protein tyrosine kinase inhibitor, TAF[[II]]250/230, TFIID, DER/top, Taf[[II]]250, hypersensitivity, hypersensitive, TAF[[II]]230, underdeveloped, top/DER, Normality, increased number, Senfgas, DEBCL, TAF[II]250, ERBB1, wa-2, C430015F12Rik, tumour of the lung, SCLC, present in greater numbers in organism, Egf, DmelCG17603, EFG-R, D830018M01Rik, Debcl, Therapeutic, Errp, Families, Erbb, Der, DER, Treatment, Lungs, D630044D05Rik, transforming growth factor-alpha receptor activity, assay, non-small cell cancer of lung, hereditary, Relatives, SCLC1, DER/torpedo, HER1, TAF1DER/faint little ball, receptor tyrosine-protein kinase erbB-1, lung neoplasms, poorly differentiated endocrine neoplasm, insensitive, D-Egf, proto-oncogene c-ErbB-1, Lung Oat Cell Carcinoma, C-erb, small cell lung carcinoma, oat cell lung carcinoma, Elp-B1, der, Elp-1, mor1, Errb1, mENA, EK2-6, ADNOS, small cell lung cancer, PIG61, small cell cancer of the lung, parenchyma of lung, epidermal growth factor-activated receptor activity, oat cell carcinoma of the lung, Oat cell carcinoma of lung, AI552599, c-erbB, EGFr, Egfr, adenocarcinomas, lung, EGF receptor activity, torpedo/Egfr, TOP, Egf-r, d-egf-r, Small Cell Carcinoma of Lung, neoplasm, neoplasm of the lung, Small Cell Carcinoma of the Lung, EGF-R, tumor of lung, Lung Small Cell Neuroendocrine Carcinoma, lung small cell neuroendocrine carcinoma, small cell neuroendocrine carcinoma of the lung, top, Torpedo/DER, oat cell carcinoma of lung, flb, oat cell carcinoma (morphologic abnormality), top/flb, small cell carcinoma of lung (disorder), tumor of the lung, oat cell carcinoma., adenocarcinoma, l(2)57EFa, lung small cell carcinoma, 9030024J15Rik, Small cell lung cancer, D-EGFR, lung oat cell carcinoma, l(2)57Ea, lung neoplasm (disease), NISBD2, tumour of lung, DER1, Elp-B1RB1, neoplasm of lung, small-cell lung cancer, Oat Cell Lung Carcinoma, Elp, pulmo, Wa5, l(2)09261, lung tumor, Oat Cell Carcinomas, TGF-alpha receptor activity, ERBB, dEGFR1, DEgfr, malignant, lung parenchyma, Small Cell Neuroendocrine Carcinoma of the Lung, small cell carcinoma of lung, CG10079, SCLC - Small cell lung cancer, no subtype (morphologic abnormality), small cell neuroendocrine carcinoma of lung, small cell carcinoma of the lung, torpedo/egfr, epidermal growth factor receptor activity, wa2, DmelCG10079, DER/top, neoplasms, egfr, Oat Cell Carcinoma, adenocarcinoma NOS (morphologic abnormality), HD-33, El, Small Cell Neuroendocrine Carcinoma of Lung, resistant, top/DER, EGFR, DER/EGFR, EGfr, EgfR, dEgfr, DER flb, ERBB1, Oat cell carcinoma of lung (disorder), wa-2, Torpedo/Egfr, tumour of the lung, Degfr, SCLC, Egf, EFG-R, pulmonary, Errp, Erbb, DEGFR, l(2)57DEFa, l(2)05351, Der, DER, Oat Cell Carcinoma of the Lung, dEGFR, Lungs, lung tumour, transforming growth factor-alpha receptor activity, DmHD-33, lung neoplasm, SCLC1, DER/torpedo, HER1DER/faint little ball, RB1, Networks, lung neoplasms, poorly differentiated endocrine neoplasm, insensitive, Kinship, Lung Oat Cell Carcinoma, determination, neoplasia, oat cell lung carcinoma, Sporadic Retinoblastomas, Elp-B1, der, Elp-1, Errb1, PPP1R50, PIG61, Mutations, small cell cancer of the lung, dmTAF[[II]]230, relapse, uninterrupted, Kinase Inhibitors, "retinoblastoma" EXACT [CSP2005:2018-3452], parenchyma of lung, Tyrosine Kinase Inhibitor, epidermal growth factor-activated receptor activity, oat cell carcinoma of the lung, AI552599, Line, RB, symptoms, 1, Life Cycle, Inhibitors, d-egf-r, present in fewer numbers in organism, Family Life Cycle, average, Small Cell Carcinoma of the Lung, increased, tumor of lung, Kinship Network, TFIID TAF250, cel, cell process disease, tumor disease, neoplasm (disease), Iprit, tyrosine kinase inhibitors, Rb, hypoplasia, small cell neuroendocrine carcinoma of the lung, Familial, oat cell carcinoma of lung, flb, allergic reaction, decreased, CG14648, tumor of the lung, Retinal Glioblastoma, 1-chloro-2-[(2-chloroethyl)sulfanyl]ethane, mustard gas, Therapies, 9030024J15Rik, Small cell lung cancer, D-EGFR, tumor, associated, Family Life Cycles, tyrphostin, NISBD2, DER1, Tyrosine Protein Kinase Inhibitors, Therapy, neoplasm of lung, screening, small-cell lung cancer, dTAF[[II]]230, Growl, pulmo, Elp, Wa5, l(2)09261, lung tumor, Oat Cell Carcinomas, DEgfr, TAF200, lung parenchyma, "Retinoblastoma NOS (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189935007], retinoblastoma, neoplastic disease, Normalcy, TAFII-250, bis(2-chloroethyl) sulfide, TAF250/230, small cell carcinoma of lung, somatic, TKI Tyrosine Kinase Inhibitors, CG10079, SCLC - Small cell lung cancer, Tyrosine, non-small cell lung cancer, bcl-2, torpedo/egfr, TAFII250, bis(2-chloroethyl)sulfane, wa2, Retinal Glioblastomas, tyrphostins, Gliomas, Filiation, non-small cell lung carcinoma (disease), neoplasms, Retinal, Lines, Bcl-2, egfr, Oat Cell Carcinoma, Familial Retinoblastoma, Retinoblastoma Eye Cancer, Retinal Gliomas, HD-33, El, Small Cell Neuroendocrine Carcinoma of Lung, Glioblastoma, resistant, Neuroblastomas, EGFR, DER/EGFR, EGfr, EgfR, dEgfr, "Retinoblastoma (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:19906005], signs, DER flb, Torpedo/Egfr, CG17603, TAF[[II]], Treatments, Tyrosine Kinase, Degfr, Hereditary Retinoblastoma, tumour disease, non-small cell carcinoma of lung, Life Cycles, Health, Taf250, pulmonary, Patient, RB - retinoblastoma, SR3-5, DEGFR, Hereditary, l(2)57DEFa, l(2)05351, hypersensitivity reaction disease, dEGFR, lung tumour, Glioma, lung neoplasm, DmHD-33, other neoplasm, TAF230, accessory, receptor tyrosine-protein kinase erbB-1, Sporadic, d230, D-Egf, Family Member, proto-oncogene c-ErbB-1, Retinal Neuroblastoma, non-small cell lung carcinoma, C-erb, small cell lung carcinoma, xBcl-2, TKI inhibitor, mor1, dTAFII250, Network, non-small cell carcinoma of the lung, Yperite, mENA, EK2-6, EfW1, small cell lung cancer, supernumerary, non-small cell cancer of the lung, eye cancer, reduced, dmTAF1, Taf230, subnumerary, sensitive, Oat cell carcinoma of lung, c-erbB, EGFr, Egfr, Eye Cancer, lung, "neuroblastoma of Retina" EXACT [NCI2004_11_17:C6956], EGF receptor activity, torpedo/Egfr, TOP, Egf-r, NSCLC - non-small cell lung cancer, Mustard gas, tiny, Small Cell Carcinoma of Lung, Retinal Glioma, 1'-thiobis(2-chloroethane), neoplasm, neoplasm of the lung, sensitivity, TAF250, Normalities, Eye Cancers, Taf200, EGF-R, Retinoblastoma Eye, TKI inhibitors, dTAF[[II]]250, Sporadic Retinoblastoma, "RB - Retinoblastoma" EXACT [SNOMEDCT_2005_07_31:134191003], Retinoblastoma Eye Cancers, Research, cell, Retinal Neuroblastomas, Lung Small Cell Neuroendocrine Carcinoma, anon-WO0118547.126, lung small cell neuroendocrine carcinoma, top, Taf1p, Torpedo/DER, tumour, growl, decreased number, oat cell carcinoma (morphologic abnormality), top/flb, bis(2-chloroethyl) sulphide, Lost, dTAF250, NSCLC, Hereditary Retinoblastomas, small cell carcinoma of lung (disorder), oat cell carcinoma., protein tyrosine kinase inhibitors, l(2)57EFa, Clients, lung small cell carcinoma, AW986256, lung oat cell carcinoma, l(2)57Ea, DmelCG14648, hypersensitivity reaction, xbcl2, Kinship Networks, TAF, "Retinoblastomas (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189934006], Family, lung neoplasm (disease), tumour of lung, sulfur mustard, oat cell carcinoma, Cancer, small, Elp-B1RB1, small-cell cancer of lung, TAF[[II]]250, Oat Cell Lung Carcinoma, findings, Family Research, 1-chloro-2-[(2-chloroethyl)thio]ethane, TGF-alpha receptor activity, ERBB, dEGFR1, malignant, Cell Lines, l(3)84Ab, Small Cell Neuroendocrine Carcinoma of the Lung, BG:DS00004.13, Client, Cell, nev, dTAF230, small cell neuroendocrine carcinoma of lung, small cell carcinoma of the lung, Family Members, neoplastic growth, epidermal growth factor receptor activity, DmelCG10079, p230, chemical analysis, "RB" EXACT [NCI2004_11_17:C7541], protein tyrosine kinase inhibitor, TAF[[II]]250/230, "Retinoblastoma (disorder)" EXACT [SNOMEDCT_2005_07_31:370967009], TFIID, DER/top, Retinoblastomas, Retinoblastoma, Taf[[II]]250, Familial Retinoblastomas, hypersensitivity, hypersensitive, TAF[[II]]230, underdeveloped, top/DER, Normality, Neuroblastoma, increased number, Glioblastomas, Senfgas, TAF[II]250, ERBB1, Oat cell carcinoma of lung (disorder), Cancers, wa-2, C430015F12Rik, tumour of the lung, disease of cellular proliferation, SCLC, present in greater numbers in organism, Egf, DmelCG17603, EFG-R, D830018M01Rik, Therapeutic, Errp, Families, Erbb, Der, DER, Oat Cell Carcinoma of the Lung, Treatment, Lungs, D630044D05Rik, transforming growth factor-alpha receptor activity, assay, non-small cell cancer of lung, Relatives, SCLC1, DER/torpedo, HER1, TAF1DER/faint little ball, receptor tyrosine-protein kinase erbB-1, lung neoplasms, poorly differentiated endocrine neoplasm, insensitive, D-Egf, proto-oncogene c-ErbB-1, C-erb, small cell lung carcinoma, oat cell lung carcinoma, Elp-B1, der, Elp-1, mor1, Errb1, mENA, EK2-6, ADNOS, small cell lung cancer, PIG61, small cell cancer of the lung, parenchyma of lung, epidermal growth factor-activated receptor activity, oat cell carcinoma of the lung, AI552599, c-erbB, EGFr, Egfr, adenocarcinomas, lung, EGF receptor activity, torpedo/Egfr, TOP, Egf-r, d-egf-r, neoplasm, neoplasm of the lung, EGF-R, tumor of lung, lung small cell neuroendocrine carcinoma, small cell neuroendocrine carcinoma of the lung, top, Torpedo/DER, oat cell carcinoma of lung, flb, oat cell carcinoma (morphologic abnormality), top/flb, tumor of the lung, oat cell carcinoma., adenocarcinoma, l(2)57EFa, lung small cell carcinoma, 9030024J15Rik, D-EGFR, lung oat cell carcinoma, l(2)57Ea, lung neoplasm (disease), NISBD2, tumour of lung, DER1, Elp-B1RB1, neoplasm of lung, small-cell cancer of lung, Elp, pulmo, Wa5, l(2)09261, lung tumor, TGF-alpha receptor activity, ERBB, dEGFR1, DEgfr, malignant, lung parenchyma, somatic, small cell carcinoma of lung, CG10079, no subtype (morphologic abnormality), small cell carcinoma of the lung, small cell neuroendocrine carcinoma of lung, torpedo/egfr, epidermal growth factor receptor activity, wa2, DmelCG10079, DER/top, neoplasms, egfr, adenocarcinoma NOS (morphologic abnormality), HD-33, El, resistant, top/DER, EGFR, DER/EGFR, EGfr, EgfR, dEgfr, DER flb, ERBB1, wa-2, Torpedo/Egfr, tumour of the lung, Degfr, SCLC, Egf, EFG-R, pulmonary, Errp, Erbb, DEGFR, l(2)57DEFa, l(2)05351, Der, DER, dEGFR, Lungs, lung tumour, transforming growth factor-alpha receptor activity, DmHD-33, lung neoplasm, SCLC1, DER/torpedo, HER1190.00.00.00.00.005860579888957434falseRB Loss in Resistant EGFR Mutant Lung Adenocarcinomas that Transform to Small Cell Lung CancerTyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs typically occurs afterafter an average of one year of continuous treatment. In a subset of patients, aA fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in resistant EGFR mutant cancers that transformed to SCLC. Consistent Further, with their similarities to classical SCLC at the genetic and gene expression levelincreased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared to resistant NSCLCs. , cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to Bcl-2 family inhibition with ABT-263 compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.2017-07-26 15:39:26EGAS00001001102960625758528EGAD00001001436EGAC00001000284