Alkylating agents activate an SLFN11-dependent vulnerability that confers PARP-1 inhibitor sensitivity in kidney cancer

BACKGROUND: PARP inhibitors have demonstrated notable clinical benefit, particularly in tumors with BRCA1/2 mutations. Clear cell renal cell carcinoma (ccRCC) carrying wild type (WT) BRCA1/2 is resistant to PARP inhibitor monotherapy. Strategies to enhance the sensitivity of BRCA1/2-WT ccRCC to PARP inhibitors remain challenging. METHODS: An in vitro chemical screen was performed to identify alkylating agents that synergize with PARP inhibition using cell viability assays. ccRCC sensitivity to individual alkylating agents was further assessed by measuring PARP-1 activity. The therapeutic effects of monotherapy and combination treatment with alkylating agents and PARP inhibitors were evaluated through DNA damage repair assays, cell viability assays, colony formation assays, ccRCC cell xenograft assays, and ccRCC patient-derived xenograft assays. Mechanistic insights and DNA repair pathway involvement were assessed using comparative expression profiling and gain- and loss-of-function approaches. RESULTS: BRCA1/2-WT ccRCC exhibits markedly higher PARP-1 activity compared to breast cancers. A subset of alkylating agents, including Temozolomide (TMZ) and Streptozocin, is identified to induce hyperactivation of PARP-1, creating a PARP-1 dependency in ccRCC cells that renders these cells sensitive to PARP inhibitors in vitro and in mice. Mechanistically, SLFN11 is selectively upregulated and boosts proteasomal degradation of BRCA1 protein in ccRCC cells. Loss of SLFN11 increases BRCA1 levels and enhances homologous recombination repair, mitigating prolonged excessive DNA damage in ccRCC cells following combination treatment with TMZ and Olaparib. SLFN11 is inversely correlated with BRCA1 expression and potentiates the therapeutic efficacy of TMZ and Olaparib combination treatment in ccRCC patient-derived xenograft models. CONCLUSION: Our findings reveal an intrinsic SLFN11-dependent vulnerability in ccRCC that synergizes with alkylating agents to induce an acquired PARP-1 dependency, thereby sensitizing BRCA1/2-WT tumors to PARP inhibition. Therefore, this work uncovers a potential therapeutic strategy for targeting SLFN11-high kidney cancers.