EGFR-Mutant SCLC Exhibits Heterogeneous Phenotypes and Resistance to Common Antineoplastic Drugs Chih-An Lin, MD, PhD, Sung-Liang Yu, PhD, Hsuan-Yu Chen,

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EGFR-Mutant SCLC Exhibits Heterogeneous Phenotypes and Resistance to Common Antineoplastic Drugs Chih-An Lin, MD, PhD, Sung-Liang Yu, PhD, Hsuan-Yu Chen, PhD, Huei-Wen Chen, PhD, Shr-Uen Lin, MS, Chia-Ching Chang, MS, Chong-Jen Yu, MD, PhD, Pan-Chyr Yang, MD, PhD, Chao-Chi Ho, MD, PhD Journal of Thoracic Oncology Volume 14, Issue 3, Pages 513-526 (March 2019) DOI: 10.1016/j.jtho.2018.11.021 Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Transformed SCLC cells derived from EGFR-mutation patients exhibited two distinct morphologies. (A) Patient CLH had a L858R mutation in EGFR. (B) Patient CLH5 had an exon 19 deletion in EGFR. Hematoxylin and eosin (HE) (upper) and immunohistochemistry (IHC) staining (lower) for TTF-1 revealed adenocarcinoma morphologies in both pretreatment specimens (A and B, left panels). The resistant biopsy specimens (A and B, right panels) uncovered SCLC morphology with positive synaptophysin staining for IHC. (C) Photomicrograph shows the morphologies of cells growing in adherent-type cells (upper) and suspension-type cells (lower). (D) Flow cytometry analysis shows CD44 highly expressed on adherent cells and weakly expressed on suspension cells. (E) CGH array analysis shows that the adherent cells and suspension cells of CLH (upper) and CLH5 (lower) underwent the same genetic alterations. Original magnification is 400×. IHC, immunohistochemistry; HE, hematoxylin-eosin; TTF-1, thyroid transcription factor 1; CGH, comparative genomic hybridization; TKI, tyrosine kinase inhibitor; FITC, fluorescein isothiocyanate; A&S, adherent and suspension cell. Journal of Thoracic Oncology 2019 14, 513-526DOI: (10.1016/j.jtho.2018.11.021) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Characterization of adherent cells and suspension cells. (A) Cell growth assay indicates that CLH-A grew faster than CLH-S, and that the CLH5-A growth rate was similar to CLH5-S. (B) Matrigel invasion assay shows that adherent cells of both CLH and CLH5 had greater invasive ability than suspension cells. (C) Anchorage-independent colony formation assay shows that CLH-S had greater colony-forming ability than CLH-A. Both CLH5-A and CLH5-S had low colony-forming ability. Statistical significance was determined by Student’s t test (*p < 0.05). (D) Conditioned medium collected from adherent cells only and co-cultured with suspension cells could enhance the invasive ability of suspension cells more than conditioned medium collected from suspension cells and the RPMI control. Data are representative of at least three independent experiments. Statistical significance was determined by Tukey's multiple comparison test (*p < 0.05). (E) Conditioned medium collected from adherent cells only and co-cultured with suspension cells could enhance the colony-forming ability of suspension cells more than conditioned medium collected from suspension cells and the RPMI control. Data are representative of at least triplicate experiments. Statistical significance was determined by Tukey's multiple comparison test (*p < 0.05). Journal of Thoracic Oncology 2019 14, 513-526DOI: (10.1016/j.jtho.2018.11.021) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 EGFR-mutant SCLC exhibited a unique gene expression cluster. The gene expression data of NSCLC and SCLC cells was obtained from the Cancer Cell Line Encyclopedia (CCLE) and the data for two EGFR-mutant SCLC cells was obtained from Niederst’s study. (A) Principal component analysis separated the clustering of EGFR-mutant SCLC from NSCLC and SCLC. (B) Hierarchical clustering analysis of the highest variance expression of 1002 genes among the NSCLC and SCLC cells and EGFR-mutant SCLC cells. The clustering revealed that EGFR-mutant SCLC has a unique gene expression cluster. Journal of Thoracic Oncology 2019 14, 513-526DOI: (10.1016/j.jtho.2018.11.021) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 TKI resistance of EGFR-mutant SCLCs is EGFR-independent and activated in the AKT/mTOR pathway. The survival curve of cells was analyzed against a first-generation TKI (gefitinib) (A, upper) and third-generation TKI (osimertinib) (B, lower). (B) Iressa inhibited the phosphorylation of EGFR, but did not block downstream signaling, including AKT and Erk. (C) Cellular phosphokinases array showed that both adherent and suspension cells exhibited an activating AKT/mTOR pathway, including phosphorylation of GSK-3a/b, AKT1/2/3, CREB, and PRAS40. CLH (C, left) and CLH5 cells (C, right). CLH-A was sensitive to MK2206 (D, left upper). CLH-S was highly sensitive to MK2206 (D, left lower). CLH5-A and CLH5-S were slightly sensitive to MK2206 (D, right). CLH-A and CLH-S were markedly reduced by combined treatment (E, left). But, modest reduction was observed in CLH5-A and CLH5-S (E, right). Journal of Thoracic Oncology 2019 14, 513-526DOI: (10.1016/j.jtho.2018.11.021) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 5 Adherent cells of EGFR-mutant SCLC exhibited higher drug tolerance than suspension cells. Cells were analyzed for their survival curve against chemotherapy drugs (etoposide plus 0.1 μmol/L cisplatin) (A and B), a bcl-2 inhibitor (ABT-263) (C and D) and pan-HDAC inhibitors (trichostatin A [TSA]) (E and F). Adherent cells exhibited higher drug tolerance to all treatments than suspension cells. TSA was a better inhibitory drug than the other two drugs. Journal of Thoracic Oncology 2019 14, 513-526DOI: (10.1016/j.jtho.2018.11.021) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 6 FK228 inhibited the tumor growth of EGFR-mutant SCLC in vitro and in vivo. Cells were analyzed for their survival curve against the HDAC inhibitor, FK228, in vitro. (A) CLH-A (upper, left), CLH-S (upper, right), CLH5-A (lower, left), and CLH5-S (lower, right). (B) The xenograft mice were generated by implanting CLH cells (for 2 × 106) and CLH5 cells (for 5 × 106). After 1 week, FK228 was intraperitoneally administered at a dose of 1 mg/kg twice per week. Tumor size and body weight was measured every 4 days. After 5 weeks, the mice were sacrificed. Data are represented as mean ± SEM (n ≥ 5). Statistical analysis was performed by unpaired Student’s t test (*p < 0.05), and revealed significant tumor growth inhibition with FK228 (p < 0.05) compared with the control. Tumor photographs (scale: 1 cm). Tissue morphology was examined by hematoxylin and eosin (HE) staining (scale: 50 μm). HDAC, histone deacetylase. Journal of Thoracic Oncology 2019 14, 513-526DOI: (10.1016/j.jtho.2018.11.021) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions