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Matthew D. Hellmann, MD, Boris Reva, PhD, Helena Yu, MD, Valerie W

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Presentation on theme: "Matthew D. Hellmann, MD, Boris Reva, PhD, Helena Yu, MD, Valerie W"— Presentation transcript:

1 Clinical and in vivo Evidence that EGFR S768I Mutant Lung Adenocarcinomas Are Sensitive to Erlotinib 
Matthew D. Hellmann, MD, Boris Reva, PhD, Helena Yu, MD, Valerie W. Rusch, MD, Naiyer A. Rizvi, MD, Mark G. Kris, MD, Maria E. Arcila, MD  Journal of Thoracic Oncology  Volume 9, Issue 10, Pages e73-e74 (October 2014) DOI: /JTO Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 Radiographic response to erlotinib in patient with EGFR S768I mutation (−40% by Response Evaluation Criteria in Solid Tumors v1.1). Journal of Thoracic Oncology 2014 9, e73-e74DOI: ( /JTO ) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 Mutation analysis of exon 20 of EGFR in the tumor sample using standard sequencing. A, Electropherogram from tumor before EGFR-tyrosine kinase inhibitor shows the mutation S768I and absence of T790M. (B) Electropherogram from tumor at acquired resistance shows both S768I and T790M. Both the wild-type and the mutant alleles are present. (C) Electropherogram corresponds to sequencing after LNA-polymerase chain reaction with a probe targeting the wild-type sequence in the region encompassing codons 789–792. With suppression of the wild-type allele, only the mutant peaks for S768I and T790M are present, indicating mutations are in-cis (same allele). Journal of Thoracic Oncology 2014 9, e73-e74DOI: ( /JTO ) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 Three-dimensional structure of the EGFR kinase domain illustrating the location of the EGFR S768I and the T790M mutations (Protein Data Bank code of EGFR structure used is 1m17). The substitution of serine for a bulky isoleucine at position 768 will result in a loss of hydrogen bonding between a side chain hydroxyl of Ser768 and a main chain oxygen of Tyr764 (circled in red). The loss of the hydrogen bond and the disturbance of the tight residue packing in the mutation position is predicted to destabilize the C-end of the alpha-helix (753–768). We hypothesize that the conformational changes at the C-end of the alpha-helix will lead to an equilibrium shift favoring an active conformation of the kinase. Importantly, the location of this change is outside the binding pocket of erlotinib (green), thereby permitting binding of erlotinib in this pocket. By contrast, the substitution of a small threonine residue for a bulky methionine in the T790M mutation, directly affects the drug binding pocket rendering the protein resistant to the drug. Journal of Thoracic Oncology 2014 9, e73-e74DOI: ( /JTO ) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

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