Novel Mutations on EGFR Leu792 Potentially Correlate to Acquired Resistance to Osimertinib in Advanced NSCLC Kai Chen, MD, Fei Zhou, MD, Wenxiang Shen,

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Novel Mutations on EGFR Leu792 Potentially Correlate to Acquired Resistance to Osimertinib in Advanced NSCLC Kai Chen, MD, Fei Zhou, MD, Wenxiang Shen, MD, Tao Jiang, MD, Xue Wu, PhD, Xiaoling Tong, MSc, Yang W. Shao, PhD, Songbing Qin, MD, Caicun Zhou, MD Journal of Thoracic Oncology Volume 12, Issue 6, Pages e65-e68 (June 2017) DOI: 10.1016/j.jtho.2016.12.024 Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Multiple mutations on EGFR Leu792 were identified in three subjects with acquired resistance to osimertinib. For each subject, the top panel shows the treatment time line. Orange triangles indicate the time points at which clinical samples were collected. Sample types are marked below. The middle panel for each subject is the integrative genomics viewer viewing of next-generation sequencing reads aligned to human hg19 reference genome. C→T, T→A, and G→C substitutions are colored red, green, and blue, respectively. Schematic diagram in the bottom panel for each subject summarizes the allelic correlation of L792F/Y/H mutations to T790M and C797S. FFPE, formalin-fixed paraffin embedded; PR, partial response; PD, progressive disease; SD, stable disease. Journal of Thoracic Oncology 2017 12, e65-e68DOI: (10.1016/j.jtho.2016.12.024) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Structural prediction of EGFR L792F/Y/H mutants in complex with osimertinib. (A) Coordinates of wild-type EGFR and osimertinib complex (identifier 4ZAU) was downloaded from the Protein Data Bank and remodeled in PyMOL software. Yellow dotted lines indicate the bonds between osimertinib and the tyrosine kinase domain of EGFR, and the amino acids that were involved in forming hydrogen bonds or covalent bonds are indicated by orange arrows. (B–D) Mutating Leu792 to Tyr (Y), Phe (F), or His (H) results in a structural collision between mutated residue and osimertinib (red disks indicated by black arrows). Journal of Thoracic Oncology 2017 12, e65-e68DOI: (10.1016/j.jtho.2016.12.024) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions