Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Cancer Sci. 2010 Sep;101(9):1933-8. doi: 10.1111/j.1349-7006.2010.01629.x.
Oncogenic mutation of epidermal growth factor receptor kinase domain is strongly associated with clinical response to tyrosine kinase inhibitors in non-small-cell lung carcinoma. Despite an initial encouraging response, patients eventually develop drug resistance and relapse. Great efforts have been made to identify the molecular mechanisms of drug resistance. With the recognition of cancer as a whole complex system, here it is proposed that cancer may evolve drug resistance in a cancer-cell-autonomous manner as well as a non-cancer-cell-autonomous manner. The former mainly arises at three levels: the robustness of the epidermal growth factor receptor signaling network; cancer epigenetic changes; or cancer genetic alteration, which may be dependent on the therapeutics methods and treatment duration. As cancer stroma plays an essential role in lung cancerigenesis, we further discuss the potential mechanisms for drug resistance development in a non-cancer-cell-autonomous manner, which may arise from the interaction between cancer cells and cancer stroma, including stromal cells and extracellular matrix.
表皮生长因子受体激酶结构域的致癌突变与非小细胞肺癌患者对酪氨酸激酶抑制剂的临床反应密切相关。尽管最初的反应令人鼓舞，但患者最终会产生耐药性并复发。人们已经做出了巨大的努力来确定耐药性的分子机制。随着人们认识到癌症是一个复杂的整体系统，这里提出癌症可能以癌症细胞自主和非癌症细胞自主的方式产生耐药性。前者主要出现在三个层面：表皮生长因子受体信号网络的稳健性；癌症表观遗传变化；或癌症基因改变，这可能取决于治疗方法和治疗持续时间。由于癌症基质在肺癌发生中起着至关重要的作用，我们进一步讨论了非癌症细胞自主耐药性发展的潜在机制，这些机制可能源于癌细胞与癌症基质之间的相互作用，包括基质细胞和细胞外基质。
