Renal cell carcinoma (RCC) accounts for about 3% of all human tumors. Alterations of oxygen, lipids, iron, and energy metabolism are involved in carcinogenesis, development, and expansion. Thirty percent of patients affected by clear cell renal cell carcinoma (ccRCC) will develop relapses or distance metastases (mRCC), dramatically reducing their life expectancy. Current first-line therapies for mRCC patients are based on treatment with immune checkpoint inhibitors (ICIs) alone and in combination with each other or with tyrosine kinase inhibitors (TKIs). However, only 20% of patients show a mild response because of innate or acquired drug resistance during long-term treatment; therefore, resistant patients need alternative first-line or second-line therapies. Pharmacological resistance represents a big problem that counteracts the efficacy of treatment by reducing overall survival (OS) in mRCC patients. Investigating the molecular mechanisms underlying drug resistance is crucial to overcoming drug insensitivity and enhancing therapeutic outcomes. In this review, we emphasize the latest and most significant studies on the molecular mechanisms that drive drug resistance in ccRCC carcinoma. Particular attention is given to the key signaling pathways involved in resistance, including those mediated by HIF, p53, Akt-mTOR, MEK–ERK cascades, Wnt signaling, autophagy, membrane transporters, ferroptosis, and non-coding RNAs. Understanding these resistance mechanisms is essential for developing new therapeutic strategies aimed to enhancing overall OS and improving the quality of life for mRCC patients. This review also discusses recent clinical trial findings on the use of specific inhibitors able to circumvent drug resistance. The data presented here could be valuable for clinicians in understanding the mechanisms of drug resistance, ultimately aiding in the management of ccRCC patients.
肾细胞癌约占人类所有肿瘤的3%。氧气、脂质、铁及能量代谢的改变参与了其癌变、发展与扩散过程。约30%的透明细胞肾细胞癌患者会出现复发或远处转移，这将显著降低其预期寿命。目前转移性肾细胞癌的一线治疗方案主要基于免疫检查点抑制剂单药治疗、联合用药或与酪氨酸激酶抑制剂联合应用。然而，由于长期治疗中出现的先天或获得性耐药，仅20%患者呈现轻微治疗反应，因此耐药患者需要替代性一线或二线治疗方案。药理学耐药是降低转移性肾细胞癌患者总生存期、削弱治疗效果的重大难题。探究耐药产生的分子机制对于克服药物不敏感性和提升治疗效果至关重要。本综述重点阐述了驱动透明细胞肾细胞癌耐药分子机制的最新重要研究，特别关注涉及耐药的关键信号通路，包括HIF、p53、Akt-mTOR、MEK–ERK级联反应、Wnt信号通路、自噬过程、膜转运蛋白、铁死亡及非编码RNA介导的途径。理解这些耐药机制对于开发旨在提高总生存期和改善患者生活质量的新型治疗策略具有重要意义。本文还讨论了近期关于使用特异性抑制剂克服耐药的临床试验发现。这些数据有助于临床医生理解耐药机制，最终为透明细胞肾细胞癌患者的治疗管理提供参考。
Molecular Mechanisms of Drug Resistance in Clear Cell Renal Cell Carcinoma
肿瘤(癌症)患者之家