경북의대 / 정주혜, 안병철*
Abstract
BACKGROUND:
Vemurafenib is a selective BRAF inhibitor (BRAFi) that has shown promising activity in BRAFV600E-positive papillary thyroid cancer (PTC). However, adverse events and resistance to a single-agent BRAFi often require discontinuation of the targeted therapy in BRAFV600E-positive PTC. Thus, this study investigated the expression of anti-apoptotic B-cell lymphoma 2 (BCL-2) family members, which are frequently overexpressed in many human cancers to inhibit apoptosis, in PTC harboring the BRAFV600E mutation after BRAFi treatment, and then evaluated the cytotoxic effects of a homology 3 domain (BH3)-mimetic in combination with a BRAFi.
METHODS:
K1 cells (BRAFV600E-positive human PTC) were treated with various concentrations of vemurafenib to investigate the effect of the BRAFi. In addition, the study analyzed the protein expression profiles of phosphorylated ERK1/2 (p-ERK 1/2) and anti-apoptotic BCL-2 family after vemurafenib treatment and selected the target anti-apoptotic protein. Antitumor effects were measured by cell counting, and effects on apoptosis were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and Western blot analysis.
RESULTS:
At a concentration of 10 μM, vemurafenib inhibited the growth of K1 cells by 49.4%. Western blot analysis following exposure to 10 μM vemurafenib revealed that p-ERK1/2 gradually decreased over 24 hours, but the expression of B-cell lymphoma-extralarge (BCL-XL) and BCL-2 increased after 12 hours of treatment. Based on this result, the K1 cells were treated with navitoclax (BCL-2/BCL-XL inhibitor) for 24 hours up to a concentration of 4 μM, which resulted in negligible effects on cell survival. However, a combination treatment of 0.5 μM navitoclax with 1 μM vemurafenib resulted in significantly enhanced cell growth inhibition and increased apoptosis.
CONCLUSIONS:
The results of the present study show that vemurafenib increased the expression of anti-apoptotic proteins of the BCL-2 family. Thus, the combination of vemurafenib with navitoclax may be effective in BRAFV600E-positive PTC treatment.
Author information
Jeong JH1, Oh JM2, Jeong SY1,2,3, Lee SW1,2,3, Lee J2,3, Ahn BC2,3.
1
1 Department of Nuclear medicine, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea.
2
2 Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
3
3 Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea.
편집위원
갑상선암 치료에 TKI가 치료에 이용되고 있으며, BRAF mutation을 가진 갑상선암에서는 selective BRAF 억제제인 vemurafenib이 이용되고 있다. 하지만 이 약제의 단독사용은 ERK rebound 현상으로 인해 치료효과의 제한과 치료에 저항성이 발생한다. 이 연구에서는 Vemurafenib 단독사용시 갑상선암세포에서 anti-apoptotic protein 발현이 증가하며 이를 표적으로 하는 약제인 navitoclax를 vemurafenib과 복합으로 사용하면 BRAFV600E양상 유두상 갑상선암에서 치료효과를 높일 수 있음을 확인하였다. 암유전자에 따라 갑상선암 치료를 최적화 할 수 있음을 보여준연구로 관련 임상가에게 관심을 끌 수 있는 연구로 보임.
2019-05-28 17:36:27