Targeted DNA damage repair: old mechanisms and new opportunities in clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) predominantly originates from renal tubular epithelial cells and displays resistance to conventional chemotherapy and radiation therapy. Multi-omics studies have delineated the intimate correlation between the molecular characteristics of ccRCC and chromosomal alterations, suggesting that interventions targeting DNA damage repair (DDR) could potentially enhance patient prognosis. This comprehensive review encompasses ccRCC epidemiology, clinical classification, diagnosis, and therapeutic strategies, with a focus on its molecular mechanisms and tumor microenvironment (TME). Special emphasis is placed on the role of DDR in ccRCC development, summarizing the latest advances in our understanding of key pathways, including mismatch repair, base excision repair, nucleotide excision repair, non-homologous end joining, and homologous recombination repair. Furthermore, the review addresses the challenges associated with current treatment approaches, such as the adaptability and resistance of ccRCC to vascular endothelial growth factor (VEGF) inhibitors and mTOR pathway inhibitors, while also exploring emerging strategies for targeting DDR in ccRCC.

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Funding

National Natural Science Foundation of China(82003114); Natural Science Foundation of Chongqing (CSTB2023NSCQ-MSX0487)