Nagarajan Nagasundaram, Guda Chittibabu
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, United States.
Center for Biomedical Informatics Research and Innovation, University of Nebraska Medical Center, Omaha, NE, United States.
Front Pharmacol. 2024 Jul 25;15:1428158. doi: 10.3389/fphar.2024.1428158. eCollection 2024.
Epidermal growth factor receptor (EGFR) gene mutations are prevalent in about 50% of lung adenocarcinoma patients. Highly effective tyrosine kinase inhibitors (TKIs) targeting the EGFR protein have revolutionized treatment for the prevalent and aggressive lung malignancy. However, the emergence of new EGFR mutations and the rapid development of additional drug resistance mechanisms pose substantial challenge to the effective treatment of NSCLC. To investigate the underlying causes of drug resistance, we utilized next-generation sequencing data to analyse the genetic alterations in different tumor genomic states under the pressure of drug selection. This study involved a comprehensive analysis of whole exome sequencing data (WES) from NSCLC patients before and after treatment with afatinib and osimertinib with a goal to identify drug resistance mutations from the post-treatment WES data. We identified five EGFR single-point mutations (L718A, G724E, G724K, K745L, V851D) and one double mutation (T790M/L858R) associated with drug resistance. Through molecular docking, we observed that mutations, G724E, K745L, V851D, and T790M/L858R, have negatively affected the binding affinity with the FDA-approved drugs. Further, molecular dynamic simulations revealed the detrimental impact of these mutations on the binding efficacy. Finally, we conducted virtual screening against structurally similar compounds to afatinib and osimertinib and identified three compounds (CID 71496460, 73292362, and 73292545) that showed the potential to selectively inhibit EGFR despite the drug-resistance mutations. The WES-based study provides additional insight to understand the drug resistance mechanisms driven by tumor mutations and helps develop potential lead compounds to inhibit EGFR in the presence of drug resistance mutations.
表皮生长因子受体（EGFR）基因突变在约50%的肺腺癌患者中普遍存在。针对EGFR蛋白的高效酪氨酸激酶抑制剂（TKIs）彻底改变了这种常见且侵袭性强的肺部恶性肿瘤的治疗方式。然而，新的EGFR突变的出现以及其他耐药机制的迅速发展，对非小细胞肺癌（NSCLC）的有效治疗构成了重大挑战。为了研究耐药的潜在原因，我们利用下一代测序数据来分析在药物选择压力下不同肿瘤基因组状态下的基因改变。本研究全面分析了非小细胞肺癌患者在接受阿法替尼和奥希替尼治疗前后的全外显子测序数据（WES），目的是从治疗后的WES数据中识别耐药突变。我们鉴定出五个与耐药相关的EGFR单点突变（L718A、G724E、G724K、K745L、V851D）和一个双突变（T790M/L858R）。通过分子对接，我们观察到G724E、K745L、V851D和T790M/L858R这些突变对与美国食品药品监督管理局（FDA）批准药物的结合亲和力产生了负面影响。此外，分子动力学模拟揭示了这些突变对结合效力的有害影响。最后，我们针对与阿法替尼和奥希替尼结构相似的化合物进行了虚拟筛选，鉴定出三种化合物（化合物识别号71496460、73292362和73292545），尽管存在耐药突变，但它们显示出选择性抑制EGFR的潜力。这项基于WES的研究为理解由肿瘤突变驱动的耐药机制提供了更多见解，并有助于开发在存在耐药突变的情况下抑制EGFR的潜在先导化合物。
