Lin Lin, Lu Qiang, Cao Ran, Ou Qiuxiang, Ma Yutong, Bao Hua, Wu Xue, Shao Yang, Wang Zhaoxia, Shen Bo
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China.
Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University Xi'an, Shaanxi, China.
Am J Cancer Res. 2020 Nov 1;10(11):4005-4015. eCollection 2020.
A growing number of progression on Osimertinib among -mutated lung cancers represents a great challenge clinically. Our study aims to gain insights into novel mechanisms of acquired resistance to Osimertinib. We performed genomic studies on 2 large independent cohorts of lung cancer patients with progressed diseases on different tyrosine kinase inhibitors (TKIs). modeling was used to study the structural mechanism of selected EGFR mutations. Compared with the 1-TKIs-resistant group, mutations C797S/G, L718Q/V, L792F/H were significantly more enriched in the Osimertinib-resistant cohort, whose sensitivities to Osimertinib were successfully predicted. Importantly, a total of 14 low-frequency mutations were exclusively or significantly observed in the Osimertinib-resistant group, 7 were predicted to dramatically reduce the binding affinity of EGFR to Osimertinib (G796S, V802F, T725M, Q791L/H, P794S/R). Analysis of pre-Osimertinib treatment samples of two patients supported that V802F and G796S were acquired during the treatment. In addition, G796S was predicted to be susceptible to gefitinib. This study represented the largest real-world data so far investigating Osimertinib resistance in -mutated lung cancer. We identified a collection of coexistent EGFR rare mutations and provided possible guidance for those patients who progressed on the first-line treatment of Osimertinib.
在EGFR突变型肺癌中，奥希替尼耐药进展的病例越来越多，这在临床上是一个巨大的挑战。我们的研究旨在深入了解奥希替尼获得性耐药的新机制。我们对两组分别接受不同酪氨酸激酶抑制剂（TKIs）治疗且病情进展的肺癌患者进行了基因组研究。采用建模方法研究了选定的EGFR突变的结构机制。与第一代TKIs耐药组相比，C797S/G、L718Q/V、L792F/H突变在奥希替尼耐药队列中显著富集，其对奥希替尼的敏感性得到成功预测。重要的是，在奥希替尼耐药组中总共专门或显著观察到14个低频EGFR突变，其中7个被预测会显著降低EGFR与奥希替尼的结合亲和力（G796S、V802F、T725M、Q791L/H、P794S/R）。对两名患者奥希替尼治疗前样本的分析支持V802F和G796S是在治疗过程中获得的。此外，G796S被预测对吉非替尼敏感。这项研究代表了迄今为止在EGFR突变型肺癌中研究奥希替尼耐药性的最大规模真实世界数据。我们鉴定出了一组共存的EGFR罕见突变，并为那些在奥希替尼一线治疗中病情进展的患者提供了可能的指导。
