Department of Oncology, Military Institute of Medicine, Warsaw, Poland.
Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.
Nat Rev Urol. 2019 Nov;16(11):655-673. doi: 10.1038/s41585-019-0233-z. Epub 2019 Oct 10.
Papillary renal cell carcinoma (pRCC) is the second most common renal cell carcinoma (RCC) subtype and accounts for 10-15% of all RCCs. Despite clinical need, few pharmacogenomics studies in pRCC have been performed. Moreover, current research fails to adequately include pRCC laboratory models, such as the ACHN or Caki-2 pRCC cell lines. The molecular mechanisms involved in pRCC development and drug resistance are more diverse than in clear-cell RCC, in which inactivation of VHL occurs in the majority of tumours. Drug resistance to multiple therapies in pRCC occurs via genetic alteration (such as mutations resulting in abnormal receptor tyrosine kinase activation or RALBP1 inhibition), dysregulation of signalling pathways (such as GSK3β-EIF4EBP1, PI3K-AKT and the MAPK or interleukin signalling pathways), deregulation of cellular processes (such as resistance to apoptosis or epithelial-to-mesenchymal transition) and interactions between the cell and its environment (for example, through activation of matrix metalloproteinases). Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies. Further studies on novel resistance biomarkers are needed to improve patient prognosis and stratification as well as drug development.
乳头状肾细胞癌 (pRCC) 是第二常见的肾细胞癌 (RCC) 亚型，占所有 RCC 的 10-15%。尽管有临床需求，但针对 pRCC 的药物基因组学研究很少。此外，目前的研究未能充分包括 pRCC 实验室模型，如 ACHN 或 Caki-2 pRCC 细胞系。与在大多数肿瘤中发生 VHL 失活的透明细胞 RCC 相比，pRCC 中涉及肿瘤发生和耐药性的分子机制更为多样化。pRCC 对多种治疗方法的耐药性是通过遗传改变（如导致异常受体酪氨酸激酶激活或 RALBP1 抑制的突变）、信号通路失调（如 GSK3β-EIF4EBP1、PI3K-AKT 和 MAPK 或白细胞介素信号通路）、细胞过程失调（如抗凋亡或上皮间质转化）以及细胞与其环境之间的相互作用（例如，通过基质金属蛋白酶的激活）来发生的。对耐药机制的深入了解将有助于药物发现并提供新的有效治疗方法。需要进一步研究新型耐药生物标志物，以改善患者的预后和分层以及药物开发。
