Molecular Mechanisms of Drug Resistance in Clear Cell Renal Cell Carcinoma

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.