Mechanisms of Acquired Resistance to AZD9291

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Mechanisms of Acquired Resistance to AZD9291 Tae Min Kim, MD, Ahnah Song, MS, Dong-Wan Kim, MD, PhD, Soyeon Kim, PhD, Yong-Oon Ahn, PhD, Bhumsuk Keam, MD, Yoon Kyung Jeon, MD, Se-Hoon Lee, MD, Doo Hyun Chung, MD, Dae Seog Heo, MD Journal of Thoracic Oncology Volume 10, Issue 12, Pages 1736-1744 (December 2015) DOI: 10.1097/JTO.0000000000000688 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Acquired resistance to AZD9291 in patient 1. A, Computed tomography of the chest showed a partial response to AZD9291 (middle; tumor reduction of 51.7% from baseline [left]) and progressive disease (right) (white arrow indicates mass in right upper lobe). B, Sanger sequencing of EGFR genes revealed the loss of EGFRT790M-mutant clones. C, The Integrated Genome Viewer revealed the depopulation of EGFRT790M-mutant clones in post-AZD9291 tumors. D, AZD9291-resistant tumors showed histologic transformation to small-cell carcinoma. Morphologically, poorly differentiated cells with a high nuclear-to-cytoplasmic ratio and neuroendocrine structure were observed in post-AZD9291 tumors (H&E, ×200). These were positive for CD56, chromogranin A, and synaptophysin by immunohistochemistry (×200). EGFR, epidermal growth factor receptor; H&E, hematoxylin and eosin. Journal of Thoracic Oncology 2015 10, 1736-1744DOI: (10.1097/JTO.0000000000000688) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Acquired resistance to AZD9291 in patient 2. A, Computed tomography of the chest showed a partial response to AZD9291 (middle; tumor reduction of 37.3% from baseline [left]) and progressive disease (right) (white arrow indicates soft tissue lesion in bone). Malignant pleural effusion decreased during response to AZD9291 but subsequently increased at progression. EGFRLREAT747del/T790M-mutant clones disappeared in post-AZD9291 tumors (B and C), and EGFR amplification remained present at disease progression (D). EGFR, epidermal growth factor receptor. Journal of Thoracic Oncology 2015 10, 1736-1744DOI: (10.1097/JTO.0000000000000688) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Acquired resistance to AZD9291 in patient 3. A, Computed tomography of the chest showed a partial response to AZD9291 (upper middle; tumor reduction of 49.2% from baseline [upper left]) and progressive disease (upper right) (white arrow indicates mass in right upper lobe). B and C, The loss of the EGFRT790M mutation was seen in post-AZD9291 tumors. D, AZD9291-resistant tumors showed focal FGFR1 amplification and high FGF2 mRNA expression as compared with baseline tumors. E, Relative mRNA expression levels of fibroblast growth factor receptor 1 (FGFR1) and basic fibroblast growth factor (FGF2) in HCC4006AR1-2 cells and parental HCC4006 cells were compared using quantitative PCR (qPCR). F, Cell proliferation assay of H1975 cells treated with 50 ng/ml FGF2 showed resistance to AZD9291. EGFR, epidermal growth factor receptor. Journal of Thoracic Oncology 2015 10, 1736-1744DOI: (10.1097/JTO.0000000000000688) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Resistance to AZD9291 in patient 4 with focal progression and EGFRT790M-mutant NSCLC cells. A, Computed tomography of the chest showed a partial response to AZD9291 (lower middle and right; tumor reduction of 66.4% from the baseline [lower left]), but focal progression at right third rib (upper) (white arrows indicate soft tissue lesion in rib [upper] and mass in left lower lobe [lower]). B, EGF mRNA levels were increased in post-AZD9291 tumors, whereas EGFR gene copy number was not significantly increased in post-AZD9291 tumors as compared with pre-AZD9291 tumors. The hgDNA and HB-EGF denote human genome DNA and heparin-binding EGF-like growth factor, respectively. C, These were similar in AZD9291-resistant H1975 cells compared with parental H1975 cells. D, EGF supplementation conferred resistance to AZD9291 in H1975 cells. EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer. Journal of Thoracic Oncology 2015 10, 1736-1744DOI: (10.1097/JTO.0000000000000688) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions