Clear cell renal cell carcinoma (ccRCC) is a common and lethal urinary malignancy characterized by its resistance to apoptosis. Despite the emerging treatment options available for ccRCC, only a small proportion of patients achieve long-term survival benefits. Previous studies have demonstrated that inducing tumor cell senescence, followed by treatment using senolytics, represents a potential strategy for triggering tumor cell apoptosis. However, it remains unclear whether this strategy is suitable for the treatment of ccRCC. Using the whole-genome CRISPR screening database Dependency Map portal (DepMap), we identified ribonucleotide reductase family member 2 (RRM2), which catalyzes the conversion of ribonucleotides to deoxyribonucleotides (dNTPs), as an essential targetable gene for ccRCC. Herein, we report that the combination of the choleretic drug osalmid targeting RRM2 and the senolytic compound navitoclax targeting BCL-XL represents a novel therapeutic approach for ccRCC. Furthermore, we have validated this approach across a panel of human ccRCC cells with different genetic backgrounds and multiple preclinical models, including cell line-derived xenografts (CDX), patient-derived xenografts (PDX), and patient-derived organoids (PDO). Mechanistically, osalmid-mediated inhibition of dNTPs generation induces cellular senescence in ccRCC, concomitant with STAT3 activation and upregulation of BCL-XL, thus rendering these cells vulnerable to navitoclax, which targets the BCL-2 protein family.
