H. R. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India 425405.
R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India 425405.
J Med Chem. 2022 Jan 27;65(2):1008-1046. doi: 10.1021/acs.jmedchem.1c00876. Epub 2021 Jul 29.
The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. This review summarizes the molecular mechanisms of resistance to Osimertinib as well as different strategies for overcoming the EGFR-dependent and EGFR-independent mechanisms of resistance, new challenges, and a future direction.
含嘧啶核心的化合物奥希替尼是唯一一种经美国食品和药物管理局批准的第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），用于靶向 threonine 790 methionine（T790M）耐药突变，同时保留野生型表皮生长因子受体（WT EGFR）。与 WT EGFR 相比，它对突变型 EGFR 的选择性几乎高 200 倍。在 EGFR 激酶结构域中，EGFR 的 tertiary cystein 797 突变为 serine 797（C797S），这阻碍了奥希替尼在晚期 EGFR 突变型非小细胞肺癌（NSCLC）患者中的治疗效果。这种 C797S 突变被认为会诱导对所有当前可逆和不可逆 EGFR TKI 的三级获得性耐药。本文综述了奥希替尼耐药的分子机制，以及克服 EGFR 依赖性和 EGFR 非依赖性耐药机制的不同策略、新的挑战和未来的方向。
