L718Q Mutation as New Mechanism of Acquired Resistance to AZD9291 in EGFR- Mutated NSCLC Melissa Bersanelli, MD, Roberta Minari, MS, PhD, Paola Bordi,

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L718Q Mutation as New Mechanism of Acquired Resistance to AZD9291 in EGFR- Mutated NSCLC Melissa Bersanelli, MD, Roberta Minari, MS, PhD, Paola Bordi, MD, Letizia Gnetti, MD, Cecilia Bozzetti, MS, Anna Squadrilli, MS, Costanza Anna Maria Lagrasta, MS, Lorena Bottarelli, MS, PhD, Ganna Osipova, MS, Enrica Capelletto, MD, Marco Mor, PhD, Marcello Tiseo, MD, PhD Journal of Thoracic Oncology Volume 11, Issue 10, Pages e121-e123 (October 2016) DOI: 10.1016/j.jtho.2016.05.019 Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Acquired resistance to AZD9291. (A) Computed tomography of the chest showed the tumor at baseline before AZD9291 treatment (left), then at partial response (middle), and progressive disease (right) after treatment with AZD9291. (B) The Integrative Genomics Viewer (Broad Institute, Cambridge, MA) revealed the mutational status of tumor at baseline (top) and after AZD9291 therapy (bottom). Next-generation sequencing was performed with TruSight Tumor 26 genes (Illumina, San Diego, CA) on the MiSeq platform (Illumina). (C) Sanger sequencing of EGFR exon 18 gene confirmed the occurrence of L718Q mutation in the tumor. Journal of Thoracic Oncology 2016 11, e121-e123DOI: (10.1016/j.jtho.2016.05.019) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Interaction of AZD9291 with EGFR. (A) Crystal structure of wild-type EGFR in complex with AZD9291 (PDB code 4ZAU). L718 directly contacts the inhibitor in an arrangement that favors the formation of a covalent bond with C797. (B) Structural model illustrating the effects of the T790M and L718Q resistance mutations (gray volumes). Although the bulkier side chain of methionine at position 790 does not interfere with AZD9291 docking, the glutamine side chain at position 718 is expected to sterically interfere with the pose of AZD9291 that allows covalent bonding to C797. Journal of Thoracic Oncology 2016 11, e121-e123DOI: (10.1016/j.jtho.2016.05.019) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions