Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan.
Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Nat Commun. 2017 Mar 13;8:14768. doi: 10.1038/ncomms14768.
Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure-activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR.
奥希替尼已被证明可克服表皮生长因子受体（EGFR）-T790M，这是第一代 EGFR 酪氨酸激酶抑制剂（EGFR-TKIs）最相关的获得性耐药。然而，C797S 突变削弱了 EGFR 位置 797 位半胱氨酸残基与奥希替尼的共价结合，导致对奥希替尼的耐药性。目前，尚无有效的治疗策略来克服 C797S/T790M/激活突变（三重突变）介导的 EGFR-TKI 耐药。在本研究中，我们发现布加替尼在体外和体内对携带三重突变的细胞有效。我们的原始计算模拟表明，布加替尼适合三重突变 EGFR 的 ATP 结合口袋。结构-活性关系分析揭示了布加替尼抑制三重突变 EGFR 的关键成分。由于表面和总 EGFR 表达的减少，布加替尼与抗 EGFR 抗体联合使用可显著提高疗效。因此，布加替尼与抗 EGFR 抗体的联合治疗是克服三重突变 EGFR 的有力候选药物。
