EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD00001007943224EGA dataset EGAD00001007943EGA<h4>Background</h4>The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.<h4>Methods</h4>Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit.<h4>Results</h4>We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy.<h4>Conclusions</h4>These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand.Hoogstrate Youri Y, Vallentgoed Wies W, Kros Johan M JM, de Heer Iris I, de Wit Maurice M, Eoli Marica M, Sepulveda Juan Manuel JM, Walenkamp Annemiek M E AME, Frenel Jean-Sebastien JS, Franceschi Enrico E, Clement Paul M PM, Weller Micheal M, van Royen Martin E ME, Ansell Peter P, Looman Jim J, Bain Earle E, Morfouace Marie M, Gorlia Thierry T, Golfinopoulos Vassilis V, van den Bent Martin M, French Pim J PJDER/faint little ball, Antigenic Determinants, l(1)G0410, para Tyrosine, beta-cat-arm, Activity, Product, determination, Laboratory, Elp-B1, der, Elp-1, Errb1, Imaging, B-cell receptor complex, Tumor, Astrocytomas, composed of, prevention, beta-cat, PIG61, Mutations, School-Age, Techniques, Readability, epitope function, Method, epidermal growth factor-activated receptor activity, AI552599, depatux-m, Pharmaceutical Product, Methazolastone, 2, 3, Kinase, Research Activity, d-egf-r, prevention and control, Laboratory Research, ARM, Arm, beta-Cat, Hypersensitivities, Priorities, treatment, increased, thymus nucleic acid, me75, CCRG81045, reference sample, antigenic determinant, membrane bound, Allergic, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Intervention Study, 5-dioxo-1H-pyrrol-1-yl)-1-oxohexyl)-N-methyl-L-valyl-N-((1S, composition, M&B39831, procedures, Giant Cell Glioblastoma, Y, Dm Arm, D17Mit170, flb, arm, T1, Astrocytoma, Upper, preventive measures, allergic reaction, Methodological Studies, medicine, Pharmaceutical, Reaction, Tyr, grade IV adult Astrocytic tumor, disease management, Therapies, 9030024J15Rik, D-EGFR, Double-Stranded DNA, Malignancies, Research Priority, deoxyribonucleic acids, DNAn, Nucleotide, B-lymphocyte receptor complex, ATP Phosphotransferases, epitope role, NISBD2, ATP, single organism signaling, DER1, Tumors, 1-d)-1, Therapy, Upper Arms, Epitope, Ligand, preventive therapy, Elp, TMZA-HE, Wa5, l(2)09261, DEgfr, 2-Amino-3-(p-hydroxyphenyl)propionic acid, Research Priorities, beta-catenin/Arm, Double-Stranded, para-Tyrosine, Giant Cell, Procedure, Tl3, antibodies, Tl2, M&B-39831, CG10079, results, 5S)-1-((2S)-2-((1S, 4S, 5-tetrazin-4(3H)-one, Tyrosine, ABBV-221, (Deoxyribonucleotide)n+m, torpedo/egfr, Temodal, KU-MEL-1, Benign, wa2, School Age, primary glioblastoma multiforme, Chemotherapy, Pharmaceutic, desoxyribose nucleic acid, activation, nucleotides, Antigenic Determinant, Research and Development, egfr, l(1)G0234, Populations, Transphosphorylases, HD-33, El, Glioblastoma, Pharmacotherapy, 5-dihydro-2, death rate, spongioblastoma multiforme, DER/EGFR, EGFR, EGfr, EgfR, content, L-Valinamide, dEgfr, L-isomer, NSC 362856, GBM, DER flb, Benign Neoplasms, common, NSC-362856, N-(6-(2, Methodological, Torpedo/Egfr, Temodar, EG:86E4.6, Methodological Study, Treatments, Degfr, Malignant Neoplasms, L isomer, NS21, Activities, immunoglobulin, B cell receptor accessory molecule complex, Grade IV Astrocytomas, Patient, Brachiums, betacat, t12687 ALR Dm, DEGFR, l(2)57DEFa, l(2)05351, ds DNA, B lymphocyte receptor complex, ALDR1, CCRG-81045, dEGFR, L-Tyrosine, DmelCG11579, School-Age Population, DmHD-33, DNA, other neoplasm, accessory, Malignant Neoplasms., D-Egf, DNS, Procedures, (Deoxyribonucleotide)n, C-erb, chemotherapy, Neoplasms, Benign Neoplasm, mor1, Temozolomide Hexyl Ester, pharmacotherapy, TMZ-Bioshuttle, Pharmacotherapies, mENA, Grade IV, Antigenic Specificity, EK2-6, Malignant, supernumerary, Deoxyribonucleic acids, Chemotherapies, antibody, Determinant, BCR complex, brachium, Deoxyribonucleic Acid, sensitive, c-erbB, EGFr, Egfr, CCRG 81045, Studies, torpedo/Egfr, EGF receptor activity, glioblastoma, TOP, Egf-r, Low, Allergic Reactions, TMZ Bioshuttle, Giant Cell Glioblastomas, immunoglobulin complex, Upper Arm, Drug Therapies, Technique, sensitivity, Phosphotransferase, Drugs, 2R)-3-(((1S)-1-carboxy-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidinyl)-3-methoxy-5-methyl-1-oxo-4-heptanyl)-N-methyl-L-valinamide, School-Age Populations, EGF-R, grade IV adult astrocytic tumor, Malignancy, Research, ligand, top, Double Stranded, Antigenic, Torpedo/DER, Brachium, Deoxyribonucleic acid, EGFRvIII, Transphosphorylase, Population, top/flb, Study, Neoplasias, Glioblastoma Multiforme, drugs, L Tyrosine, l(2)57EFa, time of survival, Clients, l(2)57Ea, Grade IV Astrocytoma, Development and Research, (Deoxyribonucleotide)m, Preparation, Tyrosin, School Age Population, l(1)2Bv, Controlled, Cancer, Pharmaceuticals, Elp-B1RB1, Allergy, Products, grade IV adult astrocytic tumour, Controlling, data, ALR, Malignant Neoplasm, cou, TGF-alpha receptor activity, ERBB, dEGFR1, DNAn+1, drug, M&B 39831, compositionality, Client, HEL-S-6, Phosphotransferases, 8-Carbamoyl-3-methylimidazo(5, l(1)arm, whole transcriptome, adult glioblastoma multiforme, Priority, Lr, 2R)-4-((2S)-2-((1S, survival, epidermal growth factor receptor activity, Arms, DmelCG10079, hypersensitivity reaction type I disease, tirosina, chemical analysis, Allergies, Research Activities, Neoplasm, DD3, background, techniques, DER/top, ds-DNA, Determinants, opsonin activity, glioblastoma multiforme, Allergic Reaction, hypersensitivity, 5-Dioxo-2, allergic hypersensitivity disease, 2R)-3-(((1S)-1-carboxy-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidi nyl)-2-methoxy-1-((1S)-1-methylpropyl)-4-oxobutyl, Reactions, distinct, top/DER, Pharmaceutic Preparations, Kinases, prophylaxis, increased number, Glioblastomas, Specificity, ERBB1, patient, Cancers, wa-2, Understanding, l(1)G0192, NSC362856, School Age Populations, introduction, upper extremity, CG11579, Drug, hypersensitivity response, extracellular, present in greater numbers in organism, Preparations, Egf, EFG-R, signalling process, Therapeutic, Errp, control, Erbb, structure, Der, DER, Desoxyribonukleinsaeure, Bra, B cell receptor activity, Treatment, 5-dihydro-1H-pyrrol-1-yl)hexanoyl)-N-methyl-L-valyl-N-((3R, pharmacologic therapy, transforming growth factor-alpha receptor activity, assay, Pharmaceutical Products, DER/torpedo, Neoplasia, HER1, methodology, Pharmaceutical PreparationVasp, VASP, Data Set., DmelCG15112, ENHANCER OF ATNSI ACTIVITY, MENA, NDPP1, l(2)02029, Enb, enb, ENA, Ena, CG15112, ENA/VASPWhole Transcriptome Shotgun Sequencing, INSDC_qualifier:unknown, RNA-seq.DER/faint little ball, D-Egf, C-erb, Elp-B1, der, Elp-1, mor1, Temozolomide Hexyl Ester, Errb1, TMZ-Bioshuttle, mENA, EK2-6, PIG61, Mutations, sensitive, epidermal growth factor-activated receptor activity, AI552599, c-erbB, EGFr, Egfr, depatux-m, CCRG 81045, torpedo/Egfr, EGF receptor activity, Methazolastone, 2, 3, TOP, Egf-r, d-egf-r, TMZ Bioshuttle, sensitivity, 2R)-3-(((1S)-1-carboxy-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidinyl)-3-methoxy-5-methyl-1-oxo-4-heptanyl)-N-methyl-L-valinamide, EGF-R, CCRG81045, 5-dioxo-1H-pyrrol-1-yl)-1-oxohexyl)-N-methyl-L-valyl-N-((1S, top, Torpedo/DER, M&B39831, flb, top/flb, allergic reaction, l(2)57EFa, 9030024J15Rik, D-EGFR, l(2)57Ea, NISBD2, DER1, Elp-B1RB1, 1-d)-1, Ligand, Elp, TMZA-HE, Wa5, l(2)09261, TGF-alpha receptor activity, ERBB, dEGFR1, DEgfr, M&B 39831, M&B-39831, CG10079, 5S)-1-((2S)-2-((1S, 4S, 5-tetrazin-4(3H)-one, ABBV-221, 8-Carbamoyl-3-methylimidazo(5, torpedo/egfr, Temodal, 2R)-4-((2S)-2-((1S, epidermal growth factor receptor activity, wa2, DmelCG10079, DER/top, egfr, 5-Dioxo-2, HD-33, El, 2R)-3-(((1S)-1-carboxy-2-phenylethyl)amino)-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidi nyl)-2-methoxy-1-((1S)-1-methylpropyl)-4-oxobutyl, 5-dihydro-2, top/DER, DER/EGFR, EGFR, EGfr, EgfR, L-Valinamide, dEgfr, NSC 362856, DER flb, ERBB1, NSC-362856, N-(6-(2, wa-2, Torpedo/Egfr, Temodar, NSC362856, Degfr, Egf, EFG-R, ligand., Errp, Erbb, DEGFR, l(2)57DEFa, l(2)05351, Der, DER, CCRG-81045, dEGFR, 5-dihydro-1H-pyrrol-1-yl)hexanoyl)-N-methyl-L-valyl-N-((3R, transforming growth factor-alpha receptor activity, DmHD-33, DER/torpedo, HER1falseena-DATASET-ErasmusMC-30-07-2021-13:54:47:012-763 - samplesIntellance-2: rRNA-minus RNA-seq2023-01-13 11:10:20EGAD00001007943960632642719EGAC00001001818EGAS00001005437