文章：

肺癌对EGFR特异性激酶抑制剂的耐药性：旁路途径激活与内源性突变体作用机制研究

Resistance of Lung Cancer to EGFR-Specific Kinase Inhibitors: Activation of Bypass Pathways and Endogenous Mutators

原文发布日期：16 October 2023

DOI: 10.3390/cancers15205009

类型: Article

开放获取: 是

英文摘要：

Epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) have changed the landscape of lung cancer therapy. For patients who are treated with the new TKIs, the current median survival exceeds 3 years, substantially better than the average 20 month survival rate only a decade ago. Unfortunately, despite initial efficacy, nearly all treated patients evolve drug resistance due to the emergence of either new mutations or rewired signaling pathways that engage other receptor tyrosine kinases (RTKs), such as MET, HER3 and AXL. Apparently, the emergence of mutations is preceded by a phase of epigenetic alterations that finely regulate the cell cycle, bias a mesenchymal phenotype and activate antioxidants. Concomitantly, cells that evade TKI-induced apoptosis (i.e., drug-tolerant persister cells) activate an intrinsic mutagenic program reminiscent of the SOS system deployed when bacteria are exposed to antibiotics. This mammalian system imbalances the purine-to-pyrimidine ratio, inhibits DNA repair and boosts expression of mutation-prone DNA polymerases. Thus, the net outcome of the SOS response is a greater probability to evolve new mutations. Deeper understanding of the persister-to-resister transformation, along with the development of next-generation TKIs, EGFR-specific proteolysis targeting chimeras (PROTACs), as well as bispecific antibodies, will permit delaying the onset of relapses and prolonging survival of patients with EGFR+lung cancer.

摘要翻译： 

表皮生长因子受体（EGFR）特异性酪氨酸激酶抑制剂（TKIs）已彻底改变肺癌治疗格局。接受新型TKIs治疗的患者目前中位生存期已超过3年，较十年前仅约20个月的平均生存率显著提升。然而尽管初始疗效显著，几乎所有接受治疗的患者最终都会因新突变出现或信号通路重编程（涉及MET、HER3、AXL等其他受体酪氨酸激酶）而产生耐药性。值得注意的是，在突变发生前存在表观遗传改变阶段，该阶段精细调控细胞周期、诱导间质表型偏倚并激活抗氧化系统。与此同时，逃逸TKI诱导凋亡的细胞（即药物耐受持久细胞）会启动内在诱变程序，其机制类似于细菌暴露于抗生素时启动的SOS反应系统。该哺乳动物系统会打破嘌呤与嘧啶的比例平衡，抑制DNA修复并促进易突变DNA聚合酶的表达，从而显著提高新突变产生的概率。深入理解持久细胞向耐药细胞的转化机制，结合新一代TKIs、EGFR特异性蛋白降解靶向嵌合体（PROTACs）及双特异性抗体的研发，将有望延缓EGFR阳性肺癌患者复发时间并延长其生存期。

原文链接：

Resistance of Lung Cancer to EGFR-Specific Kinase Inhibitors: Activation of Bypass Pathways and Endogenous Mutators