Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Neuroendocrine Differentiation in Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

  • Chang, Youjin (Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine) ;
  • Kim, Seon Ye (Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine) ;
  • Choi, Yun Jung (Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine) ;
  • So, Kwang Sup (Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine) ;
  • Rho, Jin Kyung (Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine) ;
  • Kim, Woo Sung (Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine) ;
  • Lee, Jae Cheol (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Chung, Jin-Haeng (Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine) ;
  • Choi, Chang-Min (Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine)
  • Received : 2013.05.06
  • Accepted : 2013.06.05
  • Published : 2013.09.30
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Abstract

Background: Small cell lung cancer (SCLC) transformation during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer has been suggested as one of possible resistance mechanisms. Methods: We evaluated whether SCLC transformation or neuroendocrine (NE) differentiation can be found in the cell line model. In addition, we also investigated its effect on responses to conventional chemotherapeutic drugs of the SCLC treatment. Results: Resistant cell lines to various kinds of EGFR-TKIs such as gefitinib, erlotinib, CL-387,785 and ZD6474 with A549, PC-9 and HCC827 lung adenocarcinoma cell lines were established. Among them, two resistant cell lines, A549/GR (resistant to gefitinib) and PC-9/ZDR (resistant to ZD6474) showed increased expressions of CD56 while increased synaptophysin, Rb, p16 and poly(ADP-ribose) polymerase were found only in A549/GR in western blotting, suggesting that NE differentiation occurred in A549/GR. A549/GR cells were more sensitive to etoposide and cisplatin, chemotherapeutic drugs for SCLC, compared to parental cells. Treatment with cAMP and IBMX induced synaptophysin and chromogranin A expression in A549 cells, which also made them more sensitive to etoposide and cisplatin than parental cells. Furthermore, we found a tissue sample from a patient which showed increased expressions of CD56 and synaptophysin after development of resistance to erlotinib. Conclusion: NE differentiation can occur during acquisition of resistance to EGFR-TKI, leading to increased chemosensitivity.

Keywords

References

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