Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.
Onco Targets Ther. 2014 Sep 23;7:1689-704. doi: 10.2147/OTT.S66502. eCollection 2014.
Lung cancer, mostly nonsmall cell lung cancer, continues to be the leading cause of cancer-related death worldwide. With the development of tyrosine kinase inhibitors that selectively target lung cancer-related epidermal growth factor receptor mutations, management of advanced nonsmall cell lung cancer has been greatly transformed. Improvements in progression-free survival and life quality of the patients were observed in numerous clinical studies. However, overall survival is not prolonged because of later-acquired drug resistance. Recent studies reveal a heterogeneous subclonal architecture of lung cancer, so it is speculated that the tumor may rapidly adapt to environmental changes via a Darwinian selection mechanism. In this review, we aim to provide an overview of both spatial and temporal tumor heterogeneity as potential mechanisms underlying epidermal growth factor receptor tyrosine kinase inhibitor resistance in nonsmall cell lung cancer and summarize the possible origins of tumor heterogeneity covering theories of cancer stem cells and clonal evolution, as well as genomic instability and epigenetic aberrations in lung cancer. Moreover, investigational measures that overcome heterogeneity-associated drug resistance and new assays to improve tumor assessment are also discussed.
肺癌，主要是非小细胞肺癌，仍然是全球癌症相关死亡的主要原因。随着针对肺癌相关表皮生长因子受体突变的酪氨酸激酶抑制剂的发展，晚期非小细胞肺癌的治疗已得到极大改善。许多临床研究观察到无进展生存期和患者生活质量的改善。然而，由于后来发生的药物耐药性，总生存期并未延长。最近的研究揭示了肺癌异质性亚克隆结构，因此推测肿瘤可能通过达尔文选择机制迅速适应环境变化。在这篇综述中，我们旨在概述空间和时间肿瘤异质性作为非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂耐药的潜在机制，并总结肿瘤异质性的可能起源，涵盖癌症干细胞和克隆进化理论以及肺癌中的基因组不稳定性和表观遗传异常。此外，还讨论了克服与异质性相关的药物耐药性的研究措施和改善肿瘤评估的新检测方法。
