대한두경부종양학회지 (Korean Journal of Head & Neck Oncology)

  • 제30권2호
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  • Pages.53-61
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  • 2014
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  • 1229-5183(pISSN)
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  • 2586-2553(eISSN)
대한두경부종양학회 (The Korean Society for Head and Neck Oncology)
권호 표지

BRAF(V600E) 돌연변이 갑상선 역형성암에서 BRAF(V600E) 억제에 의한 EGFR 발현 증가가 표적치료에 대한 저항성발현과 상피-간질세포이행과정에 미치는 영향분석

Mechanism of Resistance and Epithelial to Mesenchymal Transition of BRAF(V600E) Mutation Thyroid Anaplastic Cancer to BRAF(V600E) Inhibition Through Feedback Activation of EGFR

  • 변형권 (연세대학교 의과대학 이비인후과학교실) ;
  • 나휘정 (연세대학교 의과대학 이비인후과학교실) ;
  • 양연주 (연세대학교 의과대학 이비인후과학교실) ;
  • 박재홍 (순천향대학교 의과대학 이비인후과학교실) ;
  • 권형주 (연세대학교 의과대학 병리학교실) ;
  • 장재원 (연세대학교 의과대학 이비인후과학교실) ;
  • 반명진 (연세대학교 의과대학 이비인후과학교실) ;
  • 김원식 (연세대학교 의과대학 이비인후과학교실) ;
  • 신동엽 (연세대학교 의과대학 내과학교실) ;
  • 이은직 (연세대학교 의과대학 내과학교실) ;
  • 고윤우 (연세대학교 의과대학 이비인후과학교실) ;
  • 최은창 (연세대학교 의과대학 이비인후과학교실)
  • Byeon, Hyung Kwon (Department of Otorhinolaryngology, Yonsei University College of Medicine) ;
  • Na, Hwi Jung (Department of Otorhinolaryngology, Yonsei University College of Medicine) ;
  • Yang, Yeon Ju (Department of Otorhinolaryngology, Yonsei University College of Medicine) ;
  • Park, Jae Hong (Department of Otorhinolaryngology, Soonchunhyang University College of Medicine) ;
  • Kwon, Hyeong Ju (Department of Pathology, Yonsei University College of Medicine) ;
  • Chang, Jae Won (Department of Otorhinolaryngology, Yonsei University College of Medicine) ;
  • Ban, Myung Jin (Department of Otorhinolaryngology, Yonsei University College of Medicine) ;
  • Kim, Won Shik (Department of Otorhinolaryngology, Yonsei University College of Medicine) ;
  • Shin, Dong Yeob (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Lee, Eun Jig (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Koh, Yoon Woo (Department of Otorhinolaryngology, Yonsei University College of Medicine) ;
  • Choi, Eun Chang (Department of Otorhinolaryngology, Yonsei University College of Medicine)
  • 투고 : 2014.09.29
  • 심사 : 2014.10.07
  • 발행 : 2014.10.31
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초록

Background and Objectives : Anaplastic thyroid carcinoma(ATC) is a rare but highly aggressive thyroid malignancy that is associated with an extremely poor survival despite the best multidisciplinary care. BRAF(V600E) mutation is detected in about a quarter of ATC, but unlike its high treatment response to selective BRAF inhibitor (PLX4032) in metastatic melanoma, the treatment response of ATC is reported to be low. The purpose of this study is to investigate the innate resistance mechanism responsible for this low treatment response to BRAF inhibitor and its effect on epithelial-mesenchymal transition(EMT). Materials and Methods : Two ATP cell lines, 8505C and FRO were selected and treated with PLX4032 and its drug sensitivity and effects on cell migration and EMT were examined and compared. Further investigation on the changes in signals responsible for the different treatment response to PLX4032 was carried out and the same experiment was performed on both orthotopic and ectopic xenograft mouse models. Results : FRO cell line was more sensitive to PLX4032 treatment compared to 8505C cell line. The resistance to BRAF inhibition in 8505C was due to increased expression of EGFR. Effective inhibition of both EGFR and p-AKT was achieved after dual treatment with BRAF inhibitor(PLX4032) and EGFR inhibitor(Erlotinib). Similar results were confirmed on in vivo study. Conclusion : EGFR-mediated reactivation of the PI3K/AKT pathway and MAPK pathway contributes to the relative insensitivity of BRAF(V600E) mutant ATC cells to PLX4032. Dual inhibition of BRAF and EGFR leads to sustained treatment response including cell invasiveness.

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참고문헌

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