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EGF Induced RET Inhibitor Resistance in CCDC6-Retlung Cancer Cells

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EGF Induced RET Inhibitor Resistance in CCDC6-Retlung Cancer Cells Original Article Yonsei Med J 2017 Jan;58(1):9-18 https://doi.org/10.3349/ymj.2017.58.1.9 pISSN: 0513-5796 · eISSN: 1976-2437 EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells Hyun Chang1,2, Ji Hea Sung1, Sung Ung Moon1, Han-Soo Kim3, Jin Won Kim1, and Jong Seok Lee1 1Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam; 2Division of Hematology and Medical Oncology, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary’s Hospital, Incheon; 3Institute for Bio-Medical Convergence, Catholic Kwandong University College of Medicine, International St. Mary’s Hospital, Incheon, Korea. Purpose: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepa- tocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes. Materials and Methods: The effects of EGF and HGF on the susceptibility of CCDC6-RETa lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined. Results: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endotheli- al cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors. Conclusion: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer re- sistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-posi- tive lung cancer patients. Key Words: Lung cancer, RET oncogene, tyrosine kinase inhibitor, resistance, epidermal growth factor INTRODUCTION with the targeting of these proteins by small molecule inhibi- tors, has emerged as an increasingly successful treatment strat- The identification of oncogenic drivers in tumor cells, coupled egy for non-small cell lung cancer (NSCLC). NSCLC with epider- mal growth factor receptor (EGFR) gene mutation is commonly Received: October 23, 2015 Revised: May 20, 2016 sensitive to the EGFR inhibitors gefitinib and erlotinib. NSCLC Accepted: May 24, 2016 with anaplastic lymphoma kinase (ALK)-fusion is sensitive to Corresponding author: Prof. Hyun Chang, Division of Hematology and Medical On- cology, Department of Internal Medicine, Catholic Kwandong University College of the ALK inhibitor crizotinib. Lung cancer with ROS1 (ROS1 Medicine, International St. Mary’s Hospital, 25 Simgok-ro 100beon-gil, Seo-gu, proto-oncogene receptor tyrosine kinase) fusion also responds Incheon 22711, Korea. to crizotinib.1-3 Tel: 82-32-290-3878, Fax: 82-32-290-3879, E-mail: [email protected] Rearranged during transfection (RET) is a targetable driver •The authors have no financial conflicts of interest. mutation under investigation in NSCLC. RET is a receptor tyro- © Copyright: Yonsei University College of Medicine 2017 sine kinase (RTK) involved in cell proliferation, neuronal navi- This is an Open Access article distributed under the terms of the Creative Com- gation, cell migration, and cell differentiation.4 The incidence of mons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0) which permits unrestricted non-commercial use, distribution, and repro- RET fusions (KIF5B-RET or CCDC6-RET) is approximately 1% duction in any medium, provided the original work is properly cited. in patients with primary lung tumors.5 The oncogenic potential www.eymj.org 9 EGF Triggers Resistance to RET Inhibition of RET fusion has been demonstrated in vitro in transfected NI- and streptomycin (50 μg/mL), in a humidified CO2 incubator at H3T3 and Ba/F3 cells. RET inhibition with vandetanib, suni- 37°C. HUVEC cells were maintained in endothelial cell basal tinib, or sorafenib results in loss of cell viability and abrogation medium-2 and growth supplements (Lonza, Anaheim, CA, of the transformed phenotype. This result suggests that RET USA), and passages 2 through 5 were used for in vitro assays. could be a druggable target.6-8 Drilon, et al.9 reported partial re- sponses in two cases of RET fusion-positive NSCLC during Reagents phase 2 trials with the RET inhibitor cabozantinib. This result E7080, sorafenib, vandetanib, and TAE-684 were obtained from provides clinical validation of RET fusions as an oncogenic al- Seleck Chemicals. Sunitinib malate was purchased from Sigma- teration in lung cancers. Aldrich (St. Louis, MO, USA). The anti-human EGFR antibody Meanwhile, however, about 30% of all NSCLC patients with cetuximab was obtained from Merck Serono. Recombinant genetic driver alterations show intrinsic resistance to small EGF and HGF were from R&D Systems (Minneapolis, MN, molecule inhibitors.10-12 In addition, almost all patients with on- USA). cogenic drivers who respond to small molecules ultimately de- velop resistance to these agents. Therefore, understanding the Cell proliferation assays mechanism of resistance to targeted therapy is essential. LC-2/ad cells were seeded in 96-well tissue culture plates at The tumor microenvironment is gaining acceptance as an 5000 cells per well. Cells were cultured in RPMI1640 with 5% fe- essential factor of therapeutic responses. For instance, auto- tal bovine serum and incubated for 24 hours. EGF and HGF crine, paracrine, and endocrine activation of oncogenic recep- were added for incubation for 2 hours. Sunitinib, E7080, vande- tor kinases can disrupt therapeutic inhibition by sustaining ac- tanib, or sorafenib were added to each well and incubation was tivation of common intracellular signaling pathways.13 Wilson, continued for an additional 72 hours. For analysis, plates were et al.14 reported that EGF, hepatocyte growth factor (HGF), fi- incubated for 30 minutes at room temperature. Each well re- broblast growth factor (FGF), and neuregulin confer drug resis- ceived 100 μL of CellTiter-Glo Luminescent Cell Viability assay tance on tumor-derived cell lines that have oncogenic RTK sig- buffer (Promega, Madison, WI, USA), and plates were shaken naling. The EGFR family of receptors is of particular interest in for 10 minutes. Luminescence was quantified with L Max II 384 lung cancer.15 Many lung cancer cells express EGFR and MET. (Molecular Devices, Sunnyvale, CA, USA). Percent growth was These cells, along with others in their microenvironment, also calculated relative to untreated controls. Assays were carried express ligands of EGFR and MET, suggesting that these recep- out at least in triplicate with results based on three independent tors and ligands control the sensitivity of cancer cells to small experiments. The consequences of ligand exposure on drug re- molecule inhibitors in their microenvironment.14,16 Neverthe- sponse were categorized as: 1) no rescue, in which addition of less, the role of the microenvironment in the sensitivity of RET- ligand did not affect the drug response; 2) partial rescue, in fusion-positive lung cancer cells to RET-tyrosine kinase inhibi- which ligand partially abrogated the treatment response; or 3) tors (TKIs) has not been determined. complete rescue, in which ligand right-shifted the IC50 curve In the present study, we aimed to examine whether EGF and >10-fold or completely suppressed the drug response.14 HGF in the microenvironment of RET fusion-positive lung can- cer cells triggers resistance to RET inhibitors, including E7080, a RNA interference multi-targeted TKI that inhibits RET, vascular endothelial LC-2/ad cells were seeded in six-well plates and incubated growth factor receptor (VEGFR)-2, VEGFR-1, FGFR-1, and overnight. Growth medium was removed from plates before platelet-derived growth factor RTKs. transfection. After adding 500 μL of opti-MEM (Gibco), cells were transfected with EGFR-specific small interfering RNA (siRNA) (100 pmol) or negative control siRNA using 3.5 μL of MATERIALS AND METHODS Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) in accor- dance with the manufacturer’s instructions. After 6 hours, cells Cell culture were washed with PBS and incubated with growth media for 24 We selected a human lung adenocarcinoma cell line, LC-2/ad, hours. Transfected cells were co-cultured with HUVEC cells. that has a CCDC6-RET fusion.17 We identified the CCDC6-RET fusion in LC-2/ad by fusion-specific reverse transcription-poly- Co-culturing merase chain reaction (RT-PCR) (data not shown). The LC-2/ Cells were co-cultured in Transwell collagen-coated chambers ad cell line was obtained from the RIKEN cell bank (Japan). Hu- separated by 8-μm (Corning, Lowell, MA, USA) pore-size filters. man umbilical vein endothelial cells (HUVECs) were pur- LC-2/ad cells or EGFR-specific siRNA-transfected LC-2/ad cells chased from the American Type Culture Collection. LC-2/ad were seeded in 24-well plates at 8000 cells per well and incu- cells were cultured in a 1:1 mixture of RPMI1640/Ham’s F-12 bated with or without cetuximab (2 μg/mL) or gefitinib (1 μM). medium (Gibco, Carlsbad, CA, USA), supplemented with 25 After 24 hours, cells were co-cultured with or without HUVEC mM HEPES, 15% fetal bovine serum, penicillin (100 U/mL), cells (10000 cells/300 μL) in the upper chamber. After 24 hours, 10 https://doi.org/10.3349/ymj.2017.58.1.9 Hyun Chang, et al.
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