Department of Bioinformatics, Central University of South Bihar, Gaya, Bihar 824236, India.
Department of Bioinformatics, Central University of South Bihar, Gaya, Bihar 824236, India.
Biochim Biophys Acta Mol Cell Res. 2024 Jan;1871(1):119592. doi: 10.1016/j.bbamcr.2023.119592. Epub 2023 Sep 18.
Tyrosine kinase epidermal growth factor receptor (EGFR) correlates the neoplastic cell metastasis, angiogenesis, neoplastic incursion, and apoptosis. Due to the involvement of EGFR in these biological processes, it becomes a most potent target for treating non-small cell lung cancer (NSCLC). The tyrosine kinase inhibitors (TKI) have endorsed high efficacy and anticipation to patients but unfortunately, within a year of treatment, drug targets develop resistance due to mutations. The present study detected the compensatory mutations in EGFR to know the evolutionary mechanism of drug resistance. The results of this study demonstrate that compensatory mutations enlarge the drug-binding pocket which may lead to the altered orientation of the ligand (gefitinib and erlotinib) causing drug resistance. This indicates that coevolutionary forces play a significant role in fine-tuning the structure of EGFR protein against the drugs. The analysis provides insight into the evolution-induced structural aspects of drug resistance changes in EGFR which in turn be useful in designing drugs with better efficacy.
酪氨酸激酶表皮生长因子受体 (EGFR) 与肿瘤细胞转移、血管生成、肿瘤侵袭和细胞凋亡有关。由于 EGFR 参与了这些生物学过程，因此它成为治疗非小细胞肺癌 (NSCLC) 的最有效靶点。酪氨酸激酶抑制剂 (TKI) 对患者具有很高的疗效和预期，但不幸的是，在治疗一年后，由于突变，药物靶点会产生耐药性。本研究检测了 EGFR 的代偿性突变，以了解耐药性的进化机制。这项研究的结果表明，代偿性突变会扩大药物结合口袋，这可能导致配体（吉非替尼和厄洛替尼）的取向发生改变，从而导致耐药性。这表明共进化力量在精细调整 EGFR 蛋白对药物的结构方面发挥了重要作用。该分析深入了解了 EGFR 中耐药性变化的进化诱导的结构方面，这反过来又有助于设计更有效的药物。
