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Simona Coco, PhD, Anna Truini, MS, Irene Vanni, MS, Carlo Genova, MD 

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Presentation on theme: "Simona Coco, PhD, Anna Truini, MS, Irene Vanni, MS, Carlo Genova, MD "— Presentation transcript:

1 Uncommon EGFR Exon 19 Mutations Confer Gefitinib Resistance in Advanced Lung Adenocarcinoma 
Simona Coco, PhD, Anna Truini, MS, Irene Vanni, MS, Carlo Genova, MD  Journal of Thoracic Oncology  Volume 10, Issue 6, Pages e50-e52 (June 2015) DOI: /JTO Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 A, Computed tomography (CT)-scan showing left lower pleural effusion at baseline, although no measureable lesions were reported. B, CT-scan during gefitinib treatment revealed a progressive increase of the sub-centimetric nodules and increase pleural effusion. Journal of Thoracic Oncology  , e50-e52DOI: ( /JTO ) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 A, Next generation sequencing. Tumor DNA was sequenced by Ion PGM System (Life Technologies, Carlsbad, CA) using “Colon and Lung Cancer Research Panel” v.1. Integrative Genomics Viewer displays four consecutive heterozygous substitutions in the exon 19 of the EGFR ( , , , and ). These genetic variants lead to double amino acid substitution E746V-L747P. B, Sanger sequencing of EGFR transcript. Total RNA from normal surrounding lung tissue (N) and adenocarcinoma (T) snap frozen samples were retrotranscribed and bidirectional sequencing using F:5′-TTGTGGAGCCTCTTACACCC-3′ and R:5′-TGTCTTTGTGTTCCCGGACA-3′ by ABI-Prism 3130 (Life Technologies). The electropherogram of T shows four consecutive mixed peaks compared with the N cDNA, confirming the mutations in approximately 50% of tumors cells. C, Western blot analysis of EGFR phosphorylation status. Upper panel: marked increase of EGFR phosphorylated form (EGFR-P) is observed in T compared with the matched N, confirming EGFR activation in exon 19 E746V-L747P sample. Lower panel: EGFR-P in T samples from three non–small-cell lung cancer tumors with a distinct EGFR mutational status: EGFR wild type (EGFR WT); exon 19 E746V-L747P (EGFR MUT), and exon19 delE746-A750 (EGFR DEL). Notably, exon 19 E746V-L747P tumor shows high EGFR-P. Journal of Thoracic Oncology  , e50-e52DOI: ( /JTO ) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 Predicted protein structure of the double mutant E746V-L747P. This structural rearrangement allows ATP (orange and blue chemical structure) binding, even in the presence of gefitinib (purple chemical structure), in a favorable position for hydrolysis. Visual analysis of the protein structures based on native EGFR alone, in complex either with tyrosine kinase inhibitor or ATP analogue, mutated EGFR with gefitinib from Protein Data Bank ( Accessed February 10, 2015; PDB: 4WRG, 4WKQ, 4HJO, 4G5J, 4I23, 3VJO, 4I22), was carried over using the program COOT and figure was drawn using the program Chimera. Journal of Thoracic Oncology  , e50-e52DOI: ( /JTO ) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

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