Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea ; Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
Cancer Res Treat. 2016 Jan;48(1):355-64. doi: 10.4143/crt.2014.260. Epub 2015 Mar 5.
HM781-36B is a novel and irreversible pan-human epidermal growth factor receptor (HER) inhibitor with TEC cytoplasmic kinase inhibition. The aim of this study is to evaluate the antitumor activity and mechanism of action for HM781-36B in CRC cell lines.
The CRC cell lines were exposed to HM781-36B and/or oxaliplatin (L-OHP), 5-fluorouracil (5-FU), SN-38. The cell viability was examined by Cell Titer-Glo luminescent cell viability assay kit. Change in the cell cycle and protein expression was determined by flow cytometry and immunoblot analysis, respectively. Synergism between 2 drugs was evaluated by the combination index.
The addition of HM781-36B induced potent growth inhibition in both DiFi cells with EGFR overexpression and SNU-175 cells (IC50, 0.003 µM and 0.005 µM, respectively). Furthermore, HM781-36B induced G1 arrest of the cell cycle and apoptosis, and reduced the levels of HER family and downstream signaling molecules, pERK and pAKT, as well as nonreceptor/cytoplasmic tyrosine kinase, BMX. The combination of HM781-36B with 5-FU, L-OHP, or SN-38 showed an additive or synergistic effect in most CRC cells.
These findings suggest the potential roles of HM781-36B as the treatment for EGFR-overexpressing colon cancer, singly or in combination with chemotherapeutic agents. The role of BMX expression as a marker of response to HM781-36B should be further explored.
HM781-36B 是一种新型、不可逆的泛人表皮生长因子受体（HER）抑制剂，具有 TEC 细胞质激酶抑制作用。本研究旨在评估 HM781-36B 在 CRC 细胞系中的抗肿瘤活性和作用机制。
将 CRC 细胞系暴露于 HM781-36B 和/或奥沙利铂（L-OHP）、5-氟尿嘧啶（5-FU）、SN-38 中。用细胞荧光素酶发光细胞活力检测试剂盒检测细胞活力。通过流式细胞术和免疫印迹分析分别测定细胞周期变化和蛋白表达。用组合指数评估两种药物之间的协同作用。
HM781-36B 的加入在 EGFR 过表达的 DiFi 细胞和 SNU-175 细胞中均能诱导强烈的生长抑制（IC50 分别为 0.003µM 和 0.005µM）。此外，HM781-36B 诱导细胞周期 G1 期阻滞和凋亡，并降低 HER 家族和下游信号分子 pERK 和 pAKT 以及非受体/细胞质酪氨酸激酶 BMX 的水平。HM781-36B 与 5-FU、L-OHP 或 SN-38 的联合在大多数 CRC 细胞中表现出相加或协同作用。
这些发现表明 HM781-36B 具有作为治疗 EGFR 过表达结肠癌的潜力，单独使用或与化疗药物联合使用。进一步探讨 BMX 表达作为对 HM781-36B 反应的标志物的作用。
