Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with Osimertinib Chao-Chi Ho, MD, PhD, Wei-Yu Liao, MD, PhD, Chih-An Lin, Jin-Yuan.

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Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with Osimertinib Chao-Chi Ho, MD, PhD, Wei-Yu Liao, MD, PhD, Chih-An Lin, Jin-Yuan Shih, MD, PhD, Chong-Jen Yu, MD, PhD, James Chih-Hsin Yang, MD, PhD Journal of Thoracic Oncology Volume 12, Issue 3, Pages 567-572 (March 2017) DOI: 10.1016/j.jtho.2016.11.2231 Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Cells grown from malignant pleural effusion of a patient at the time of progression while the patient was taking osimertinib, with an exon 19 deletion plus T70M plus BRAF V600E. (A) Morphologic features of the cell, including the attached confluent growth, are shown. (B) Genotyping of this cell was done with matrix-assisted laser desorption ionization–time of flight mass spectrometry and showed exon 19 Del plus T790M plus BRAF V600E. Journal of Thoracic Oncology 2017 12, 567-572DOI: (10.1016/j.jtho.2016.11.2231) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 The effect of BRAF V600E inhibitor LGX818 (encorafenib) and T790M inhibitor AZD9291 (osimertinib) on EGFR pathway signaling in this exon 19 Del plus T790M plus BRAF V600E cell. Data depict Western blot analysis of various signaling proteins in the presence or absence of encorafenib and/or osimertinib. α-Tubulin was included as a control. No AKT phosphorylation was detected. LGX818 suppresses MEK signaling but had no significant effect on ERK phosphorylation. Combined LGX818 and AZD9291 had an effect on both MEK and ERK. H1975 cells harboring L858R plus T790M were used as a control. Journal of Thoracic Oncology 2017 12, 567-572DOI: (10.1016/j.jtho.2016.11.2231) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Defective colony formation of this cell after treatment with the BRAF V600E inhibitor LGX818 (encorafenib) and the T790M inhibitor AZD9291 (osimertinib). (A) Clonogenicity in a two-dimensional culture dish revealed defective colony formation after LGX818 treatment. Combined LGX818 and AZD9291 treatment had a more potent effect. (B) Colony numbers from (A) are illustrated graphically. Journal of Thoracic Oncology 2017 12, 567-572DOI: (10.1016/j.jtho.2016.11.2231) Copyright © 2016 International Association for the Study of Lung Cancer Terms and Conditions