Southern Medical University, Guangzhou, People's Republic of China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
J Thorac Oncol. 2018 Sep;13(9):1415-1421. doi: 10.1016/j.jtho.2018.05.024. Epub 2018 May 30.
The third-generation EGFR tyrosine kinase inhibitor osimertinib has been approved in many countries to treat advanced NSCLC in patients with the EGFR T790M mutation. As the development of acquired resistance is inevitable, it is urgent that the mechanisms of such resistance be clarified.
DNA samples from a cohort of 340 patients with lung adenocarcinoma who were taking osimertinib were subjected to next-generation sequencing and screened in terms of the frequencies of the L792H and G796R mutations. Ba/F3 cells stably expressing the EGFR L858R/T790M mutations (in cis) with either the L792H or G796R mutation were created to investigate the impact of the two novel mutations on EGFR tyrosine kinase inhibitors and other potential drug combinations in vitro. Structural analyses were performed by using Schrödinger/Maestro software (version 11.1.012, Schrödinger LLC, Cambridge, MA).
L792H and G796R were detected in 1.76% (six of 340) and 0.56% (two of 340) patients with lung adenocarcinoma treated with osimertinib, respectively. The introduction of L792H or G796R mutations against an L858R/T790M background caused dramatic reductions in osimertinib sensitivity. Structural modeling showed that mutations in cis with T790M either forced the ligand (osimertinib) to rotate out (breaking the binding) or pulled the hinge loop (breaking the hinge). Various other drug combinations. including cetuximab with EAI045, failed to inhibit either cis mutant effectively.
The EGFR L858R/T790M/L792H and L858R/T790M/G796R mutations conferred resistance to osimertinib both in vitro and in silico. For patients in whom the two resistance mutations occur at low frequency, more precise treatment strategies and additional combinational approaches are required.
第三代 EGFR 酪氨酸激酶抑制剂奥希替尼已在许多国家获得批准，用于治疗携带 EGFR T790M 突变的晚期 NSCLC 患者。由于获得性耐药的发展是不可避免的，因此迫切需要阐明这种耐药的机制。
对 340 名接受奥希替尼治疗的肺腺癌患者的 DNA 样本进行下一代测序，并筛选 L792H 和 G796R 突变的频率。构建稳定表达 EGFR L858R/T790M（顺式）突变且带有 L792H 或 G796R 突变的 Ba/F3 细胞，以研究这两种新突变对 EGFR 酪氨酸激酶抑制剂和其他潜在药物组合的影响。使用 Schrödinger/Maestro 软件（版本 11.1.012，Schrödinger LLC，马萨诸塞州剑桥）进行结构分析。
在接受奥希替尼治疗的肺腺癌患者中，分别检测到 1.76%（340 例中有 6 例）和 0.56%（340 例中有 2 例）的 L792H 和 G796R 突变。在 L858R/T790M 背景下引入 L792H 或 G796R 突变会导致奥希替尼敏感性显著降低。结构建模表明，T790M 顺式突变要么迫使配体（奥希替尼）旋转出（打破结合），要么拉动铰链环（打破铰链）。包括 cetuximab 与 EAI045 的各种其他药物组合均未能有效抑制顺式突变体。
EGFR L858R/T790M/L792H 和 L858R/T790M/G796R 突变在体外和体内均赋予奥希替尼耐药性。对于这两种耐药突变频率较低的患者，需要更精确的治疗策略和额外的联合治疗方法。
