Medical Oncology Unit, University Hospital of Parma, 43126, Parma, Italy; Department of Medical Oncology, Amsterdam University Medical Center, VU University, 1081 HV Amsterdam, the Netherlands.
The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200000, Israel.
Drug Resist Updat. 2019 Jan;42:1-11. doi: 10.1016/j.drup.2018.11.002. Epub 2018 Nov 28.
The introduction of EGFR-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment and prognosis of non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations. However, these patients display disease progression driven by the onset of acquired mechanisms of drug resistance that limit the efficacy of EGFR-TKI to no longer than one year. Moreover, a small fraction of EGFR-mutated NSCLC patients does not benefit from this targeted treatment due to primary (i.e. intrinsic) mechanisms of resistance that preexist prior to TKI drug treatment. Research efforts are focusing on deciphering the distinct molecular mechanisms underlying drug resistance, which should prompt the development of novel antitumor agents that surmount such chemoresistance modalities. The capability of microRNAs (miRNAs) to regulate the expression of many oncogenic pathways and their central role in lung cancer progression, provided new directions for research on prognostic biomarkers, as well as innovative tools for predicting patients' response to systemic therapies. Recent evidence suggests that modulation of key miRNAs may also reverse oncogenic signaling pathways, and potentiate the cytotoxic effect of anti-cancer therapies. In this review, we focus on the putative emerging role of miRNAs in modulating drug resistance to EGFR-TKI treatment in EGFR-mutated NSCLC. Moreover, we discuss the current implications of miRNAs analyses in the clinical setting, using both tissue and liquid biopsies, as well as the future potential use of miRNA-based therapies in overcoming resistance to targeted agents like TKIs.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）的引入彻底改变了携带 EGFR 突变的非小细胞肺癌（NSCLC）患者的治疗和预后。然而，这些患者由于获得性耐药机制的出现而导致疾病进展，从而限制了 EGFR-TKI 的疗效，使其使用时间不超过一年。此外，由于存在原发性（即内在）耐药机制，一小部分 EGFR 突变型 NSCLC 患者不能从这种靶向治疗中获益。研究工作的重点是破译耐药性背后的不同分子机制，这应该促使开发新的抗肿瘤药物来克服这种化疗耐药模式。microRNAs（miRNAs）调控许多致癌途径表达的能力及其在肺癌进展中的核心作用，为预后生物标志物的研究以及预测患者对系统治疗反应的创新工具提供了新的方向。最近的证据表明，关键 miRNAs 的调节也可能逆转致癌信号通路，并增强抗癌治疗的细胞毒性作用。在这篇综述中，我们重点关注 miRNAs 在调节 EGFR-TKI 治疗 EGFR 突变型 NSCLC 耐药中的潜在新兴作用。此外，我们还讨论了使用组织和液体活检进行 miRNA 分析在临床环境中的当前意义，以及 miRNA 治疗在克服靶向药物（如 TKI）耐药方面的未来潜在用途。
