Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore.
Int J Mol Sci. 2023 Feb 18;24(4):4126. doi: 10.3390/ijms24044126.
The advent of tyrosine kinase inhibitors (TKIs) for treating epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) has been a game changer in lung cancer therapy. However, patients often develop resistance to the drugs within a few years. Despite numerous studies that have explored resistance mechanisms, particularly in regards to collateral signal pathway activation, the underlying biology of resistance remains largely unknown. This review focuses on the resistance mechanisms of EGFR-mutated NSCLC from the standpoint of intratumoral heterogeneity, as the biological mechanisms behind resistance are diverse and largely unclear. There exist various subclonal tumor populations in an individual tumor. For lung cancer patients, drug-tolerant persister (DTP) cell populations may have a pivotal role in accelerating the evolution of tumor resistance to treatment through neutral selection. Cancer cells undergo various changes to adapt to the new tumor microenvironment caused by drug exposure. DTP cells may play a crucial role in this adaptation and may be fundamental in mechanisms of resistance. Intratumoral heterogeneity may also be precipitated by DNA gains and losses through chromosomal instability, and the role of extrachromosomal DNA (ecDNA) may play an important role. Significantly, ecDNA can increase oncogene copy number alterations and enhance intratumoral heterogeneity more effectively than chromosomal instability. Additionally, advances in comprehensive genomic profiling have given us insights into various mutations and concurrent genetic alterations other than EGFR mutations, inducing primary resistance in the context of tumor heterogeneity. Understanding the mechanisms of resistance is clinically crucial since these molecular interlayers in cancer-resistance mechanisms may help to devise novel and individualized anticancer therapeutic approaches.
酪氨酸激酶抑制剂 (TKIs) 的出现改变了表皮生长因子受体 (EGFR) 突变型非小细胞肺癌 (NSCLC) 的治疗格局。然而，患者通常在几年内就会对药物产生耐药性。尽管有许多研究探索了耐药机制，特别是关于旁路信号通路激活，但耐药的潜在生物学机制仍知之甚少。本综述从肿瘤内异质性的角度聚焦 EGFR 突变型 NSCLC 的耐药机制，因为耐药的生物学机制多种多样，且在很大程度上仍不清楚。在个体肿瘤中存在各种亚克隆肿瘤群体。对于肺癌患者，药物耐受持久细胞 (DTP) 群体可能通过中性选择在加速肿瘤对治疗的耐药性进化方面发挥关键作用。癌细胞会发生各种变化以适应药物暴露引起的新肿瘤微环境。DTP 细胞可能在这种适应中发挥关键作用，并且可能是耐药机制的基础。肿瘤内异质性也可能由染色体不稳定性引起的 DNA 增益和丢失引发，并且额外染色体 DNA (ecDNA) 的作用可能很重要。值得注意的是，ecDNA 可以比染色体不稳定性更有效地增加致癌基因拷贝数改变并增强肿瘤内异质性。此外，全面基因组分析的进展使我们深入了解了 EGFR 突变以外的各种突变和并发遗传改变，这些改变在肿瘤异质性背景下导致原发性耐药。了解耐药机制在临床上至关重要，因为这些癌症耐药机制中的分子层可能有助于设计新的个体化抗癌治疗方法。
