Dell'Atti Lucio, Bianchi Nicoletta, Aguiari Gianluca
Division of Urology, Ospedali Riuniti University Hospital, 60126 Ancona, Italy.
Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
Cancers (Basel). 2022 Jul 25;14(15):3616. doi: 10.3390/cancers14153616.
Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) in combination with immuno-oncology (IO) therapy or IO-IO treatments. Second-line therapy involves the use of other TKIs, immunotherapeutic drugs, and mTOR inhibitors. Nevertheless, many patients treated with mTOR and TK inhibitors acquire drug resistance, making the therapy ineffective. Therefore, the research of new therapeutic targets is crucial for improving the overall survival and quality of life of mRCC patients. The investigation of the molecular basis of RCC, especially in clear cell renal cell carcinoma (ccRCC), has led to the identification of different signaling pathways that are involved in renal carcinogenesis. Most of ccRCCs are associated with mutation in gene, which mediates the degradation of hypoxia-inducible factors (HIFs), that, in turn, regulate the pathways related to tumorigenesis, including angiogenesis and invasion. Renal tumorigenesis is also associated with the activation of tyrosine kinases that modulate the PI3K-Akt-mTOR pathway, promoting cell proliferation and survival. In ccRCC, the abnormal activity of mTOR activates the MDM2 protein, which leads to the degradation of tumor suppressor p53 via proteasome machinery. In addition, p53 may be degraded by autophagy in a mechanism involving the enzyme transglutaminase 2 (TG2). Suppression of wild-type p53 promotes cell growth, invasion, and drug resistance. Finally, the activation of ferroptosis appears to inhibit cancer progression in RCC. In conclusion, these pathways might represent new therapeutic targets for mRCC.
转移性肾细胞癌（mRCC）患者自确诊后5年的总生存率低于10%。目前，mRCC患者的一线治疗基于能够抑制酪氨酸激酶受体（TKI）的抗血管生成药物，并联合免疫肿瘤学（IO）疗法或IO-IO治疗。二线治疗则使用其他TKI、免疫治疗药物和mTOR抑制剂。然而，许多接受mTOR和TK抑制剂治疗的患者会产生耐药性，导致治疗无效。因此，研究新的治疗靶点对于提高mRCC患者的总生存率和生活质量至关重要。对肾细胞癌分子基础的研究，尤其是在透明细胞肾细胞癌（ccRCC）中的研究，已导致鉴定出参与肾癌发生的不同信号通路。大多数ccRCC与 基因的突变有关，该基因介导缺氧诱导因子（HIFs）的降解，而HIFs反过来又调节与肿瘤发生相关的通路，包括血管生成和侵袭。肾肿瘤发生还与调节PI3K-Akt-mTOR通路的酪氨酸激酶的激活有关，从而促进细胞增殖和存活。在ccRCC中，mTOR的异常活性激活MDM2蛋白，导致肿瘤抑制因子p53通过蛋白酶体机制降解。此外，p53可能通过一种涉及转谷氨酰胺酶2（TG2）的自噬机制被降解。野生型p53的抑制促进细胞生长、侵袭和耐药性。最后，铁死亡的激活似乎抑制了RCC中的癌症进展。总之，这些通路可能代表了mRCC的新治疗靶点。
