Kim Soo Jin, Lee Kyunghyeon, Park Jaewoo, Park Miso, Kim U Ji, Kim Se-Mi, Ryu Keun Ho, Kang Keon Wook
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826 Republic of Korea.
CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation, 16995, Gyeonggi-do, Republic of Korea.
Toxicol Res. 2022 Aug 22;39(1):61-69. doi: 10.1007/s43188-022-00146-0. eCollection 2023 Jan.
Lung cancer is the leading cause of cancer death. Although docetaxel has been used as a second- or third-line treatment for non-small cell lung cancer (NSCLC), the objective response rate is less than 10%. Hence, there is a need to improve the clinical efficacy of docetaxel monotherapy; combination therapy should be considered. Here, we show that CKD-516, a vascular disruption agent, can be combined with docetaxel to treat epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant NSCLC. CKD-516 was orally bioavailable; neither CKD-516 nor docetaxel affected the mean plasma concentration-time profile or pharmacokinetic parameters of the other drug. CKD-516 and docetaxel synergistically inhibited the growth of H1975 (with an L858R/T790M double mutation of EGFR) and A549 (with a KRAS mutation) lung cancer cell lines. In addition, docetaxel plus CKD-516 delayed tumor growth in-and extended the lifespan of-tumor-bearing mice. Thus, combination CKD-516 and docetaxel therapy could be used to treat EGFR-TKI-resistant NSCLC.
肺癌是癌症死亡的主要原因。尽管多西他赛已被用作非小细胞肺癌（NSCLC）的二线或三线治疗药物，但其客观缓解率低于10%。因此，有必要提高多西他赛单药治疗的临床疗效；应考虑联合治疗。在此，我们表明，血管破坏剂CKD-516可与多西他赛联合用于治疗表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）耐药的NSCLC。CKD-516具有口服生物利用度；CKD-516和多西他赛均不影响另一种药物的平均血浆浓度-时间曲线或药代动力学参数。CKD-516和多西他赛协同抑制H1975（具有EGFR的L858R/T790M双突变）和A549（具有KRAS突变）肺癌细胞系的生长。此外，多西他赛加CKD-516可延缓荷瘤小鼠的肿瘤生长并延长其生存期。因此，CKD-516与多西他赛联合治疗可用于治疗EGFR-TKI耐药的NSCLC。
