Heterogeneity of Genetic Changes Associated with Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancer Soyeon Kim, PhD, Tae Min Kim, MD, PhD,

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Heterogeneity of Genetic Changes Associated with Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancer Soyeon Kim, PhD, Tae Min Kim, MD, PhD, Dong-Wan Kim, MD, PhD, Heounjeong Go, MD, Bhumsuk Keam, MD, Se-Hoon Lee, MD, PhD, Ja-Lok Ku, PhD, Doo Hyun Chung, MD, PhD, Dae Seog Heo, MD, PhD Journal of Thoracic Oncology Volume 8, Issue 4, Pages 415-422 (April 2013) DOI: 10.1097/JTO.0b013e318283dcc0 Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 ALK fusion transcripts and ALK mutations. (A) Virtual gel electro-phoresis was performed on multiple RT-PCR products derived from patients’ specimens (n = 7) and NSCLC cells (n = 3). The suffix “B” indicates tumor specimens before crizotinib treatment. Four and two patients harbored EML4-ALK variants 1 and 3, respectively. The KIF5B-ALK fusion transcript was detected in an SNU7 patient. (B) Electropherograms showed the 4713 G→C and 4493 C→A mutations in an SNU1 patient. (C) L1196M and G1269A were detected by mutation-specific PCR assays. ALK, anaplastic lymphoma kinase; NSCLC, non–small-cell lung cancer; RT-PCR, reverse transcription–polymerase chain reaction. Journal of Thoracic Oncology 2013 8, 415-422DOI: (10.1097/JTO.0b013e318283dcc0) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 L1196M and G1269A mutant clones are resistant to crizotinib treatment. (A) 293T cells transiently transfected with EML4-ALK WT, L1196M, and G1269A constructs showed ineffective suppression of phospho-ALK in crizotinib-resistant clones. (B) Ba/F3 cells were transformed to express wild-type EML4-ALK or EML4-ALK harboring L1196M or G1269A mutations. The parental Ba/F3 cells with IL-3 or the EML4-ALK-expressing Ba/F3 cells without IL-3 were treated with crizotinib. Cell cytotoxicity was measured using CCK-8. The IC50 values were 14.874, 0.049, 0.216, and 0.482 µM in Ba/F3+IL3, Ba/F3-WT, Ba/F3-L1196M, and Ba/F3-G1269A cells, respectively. ALK, anaplastic lymphoma kinase; IL, interleukin. Journal of Thoracic Oncology 2013 8, 415-422DOI: (10.1097/JTO.0b013e318283dcc0) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 ALK mutant NSCLC cells are resistant to crizotinib treatment. (A) A cell viability assay was plotted for H3122, SNU-2535, and H3122 CR1 cells (crizotinib-resistant) treated with or without crizotinib for 72 hours. (B) Phospho-ALK downstream signals were less suppressed after treatment with crizotinib in SNU-2535 and H3122 CR1 cells than in H3122 cells. (C) Apoptosis induction was high in H3122 cells compared with that in SNU-2535 cells treated with crizotinib. ALK, anaplastic lymphoma kinase; NSCLC, non–small-cell lung cancer. Journal of Thoracic Oncology 2013 8, 415-422DOI: (10.1097/JTO.0b013e318283dcc0) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Heterogeneous genetic alterations in patients with acquired crizotinib resistance. (A) The SNU5 patient had an average ALK copy number gain of 8.5 in the post-crizotinib specimen compared with 2.0 in the pre-crizotinib specimen. (B) EGFR high polysomy was observed in the SNU5 patient in the post-crizotinib sample. (C) Amphiregulin and (D) EGF concentrations in patients and NSCLC cells. NSCLC, non–small-cell lung cancer. Journal of Thoracic Oncology 2013 8, 415-422DOI: (10.1097/JTO.0b013e318283dcc0) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions