S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
In vitro anticancer activity of phosphatidylinositol 3-kinase alpha selective inhibitor BYL719 in head and neck cancer : 두경부 편평세포암 세포주에서 포스파티딜 이노시톨 3 –키나제 알파 특이 억제제의 항암효과
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2014. 8. 허대석.
- Introduction: Activating mutations of the PIK3CA gene occur frequently in head and neck squamous cell carcinoma. The purpose of this study was to explore the antiproliferative effect of BYL719, a specific inhibitor for phosphatidylinositol 3-kinase (PI3K) p110α, in human head and neck cancer cell lines, as a single agent or in combination with the irreversible EGFR tyrosine kinase inhibitor (TKI), dacomitinib.
Material and Methods: Six head and neck cancer cell lines consisting of 2 PIK3CA mutant cell lines, SNU-1076 and Detroit562 and 4 PIK3CA wild type cell lines, SNU-1066, SNU-1041, FaDu and SCC25, were analysed. The inhibitory effect of BYL719 on cellular proliferation was assessed using the tetrazolium bromide [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide] assay. The cell cycle at various concentrations of BYL719 was analyzed by flow cytometry, and the protein expression of downstream molecules determined by Western blot analysis.
Results: The PIK3CA mutant cell lines (SNU-1076 and Detroit562) were more sensitive to BYL719 than the PIK3CA wild type cell lines (SNU-1066, SNU-1041, FaDu and SCC25). Following BYL719 treatment, all PIK3CA wild type cell lines, except the SNU-1066 cell line, exhibited higher IC50 values (1.13, 20.65, 19.67 and 49.30 μM, SNU-1066, SNU-1041, FaDu and SCC25, respectively) compared with the PIK3CA mutant cell lines (6.82 and 1.10 μM, SNU-1076 and Detroit562, respectively). Administration of BYL719 in the PIK3CA mutant cell lines induced cell cycle G0/1 arrest and resulted in increased apoptosis in a dose dependant manner. Furthermore, the administration of BYL719 in the PIK3CA mutant cell lines reduced the level of p-mTOR, p-AKT and p-S6 expression indicating the down regulating of downstream signaling. BYL719 combined with dacomitinib had a synergistic inhibitory effect.
Conclusion: BYL719, PI3K alpha selective blocker, could be a promising treatment for head and neck cancer as a single agent or in combination with dacomitinib. The beneficial effects of BYL719 in in vitro studies for head and neck cancer warrant a further clinical investigation.