Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, 05505, South Korea.
Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, 05505, South Korea.
Target Oncol. 2018 Jun;13(3):389-398. doi: 10.1007/s11523-018-0568-z.
Despite remarkable activity in epidermal growth factor receptor (EGFR)-mutant lung cancer patients, the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) is limited by the emergence of acquired resistance, which is mostly caused by a secondary T790M mutation. Fortunately, newly developed, mutant-selective EGFR-TKIs against T790M have been proven as an effective therapeutic approach although only osimertinib has received the FDA approval until now.
To determine the in vitro and in vivo efficacy of a new EGFR TKI, OBX1-012 in cells with mutant EGFR.
Effects of OBX1-012 on cellular viability and EGFR-related signaling were determined in EGFR-mutant non-small cell lung cancer (NSCLC) cells, including cells harboring T790M mutations. In addition, in vivo efficacy of OBX1-012 was evaluated in xenograft models.
We report the discovery and preclinical assessment of another novel, mutant-selective EGFR-TKI, OBX1-012. Compared with other mutant-selective EGFR-TKIs such as olumitinib and osimertinib, it showed similar potency and selectivity for mutant EGFR. OBX1-012 treatment was highly effective against human EGFR-mutant lung cancer models with or without EGFR T790M, not only in vitro but also in vivo. However, OBX1-012 like other EGFR-TKIs failed to exhibit efficacy for the exon 20 insertion mutation or C797S mutation, which was generated by site-directed mutagenesis and stable transfection of Ba/F3 cells.
These results identify OBX1-012 as a highly effective, mutant-selective EGFR-TKI for the treatment of T790M-mediated resistance in NSCLC.
尽管表皮生长因子受体（EGFR）突变型肺癌患者的治疗效果显著，但 EGFR 酪氨酸激酶抑制剂（TKI）的临床疗效受到获得性耐药的限制，而获得性耐药主要是由二次 T790M 突变引起的。幸运的是，新开发的针对 T790M 的突变选择性 EGFR-TKI 已被证明是一种有效的治疗方法，尽管迄今为止只有奥希替尼获得了 FDA 批准。
确定新型 EGFR TKI OBX1-012 在具有突变 EGFR 的细胞中的体外和体内疗效。
在携带 T790M 突变的 EGFR 突变型非小细胞肺癌（NSCLC）细胞中，包括细胞中，测定 OBX1-012 对细胞活力和 EGFR 相关信号的影响。此外，还在异种移植模型中评估了 OBX1-012 的体内疗效。
我们报告了另一种新型、突变选择性 EGFR-TKI OBX1-012 的发现和临床前评估。与其他突变选择性 EGFR-TKI 如 olumitinib 和 osimertinib 相比，它对突变型 EGFR 具有相似的效力和选择性。OBX1-012 治疗对具有或不具有 EGFR T790M 的人 EGFR 突变型肺癌模型具有高度疗效，不仅在体外，而且在体内也是如此。然而，与其他 EGFR-TKIs 一样，OBX1-012 未能对通过定点突变和 Ba/F3 细胞的稳定转染产生的外显子 20 插入突变或 C797S 突变显示出疗效。
这些结果表明 OBX1-012 是一种高度有效的、突变选择性的 EGFR-TKI，可用于治疗 NSCLC 中的 T790M 介导的耐药性。
