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Alkylating agents activate an SLFN11-dependent vulnerability that confers PARP-1 inhibitor sensitivity in kidney
Chenliang Wang1, Ming Zhu1, Lei Bao1
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
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.
Insights
Clear cell renal cell carcinoma (ccRCC) with wild type BRCA1/2 is resistant to PARP inhibitors. Alkylating agents like Temozolomide synergize with PARP inhibitors by creating a dependency, sensitizing ccRCC tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PARP inhibitors show clinical benefit in BRCA1/2-mutated cancers.
- Clear cell renal cell carcinoma (ccRCC) with wild-type BRCA1/2 (WT) is resistant to PARP inhibitor monotherapy.
- Enhancing PARP inhibitor sensitivity in WT ccRCC remains a challenge.
Purpose of the Study:
- To identify therapeutic strategies to sensitize BRCA1/2-WT ccRCC to PARP inhibitors.
- To explore the synergistic effects of alkylating agents and PARP inhibitors in ccRCC.
- To elucidate the underlying mechanisms of PARP inhibitor resistance and resensitization in ccRCC.
Main Methods:
- In vitro chemical screen to identify synergistic alkylating agents with PARP inhibitors.
- Assessed ccRCC sensitivity to alkylating agents by measuring PARP-1 activity.
- Evaluated therapeutic effects using DNA damage repair assays, cell viability assays, xenograft models, and mechanistic studies.
Main Results:
- BRCA1/2-WT ccRCC exhibits higher PARP-1 activity than breast cancers.
- Temozolomide (TMZ) and Streptozocin hyperactivate PARP-1, creating dependency and sensitizing ccRCC cells to PARP inhibitors.
- SLFN11 upregulation degrades BRCA1, enhancing sensitivity to combination therapy with TMZ and Olaparib in ccRCC models.
Conclusions:
- An intrinsic SLFN11-dependent vulnerability in ccRCC synergizes with alkylating agents.
- This synergy induces acquired PARP-1 dependency, sensitizing BRCA1/2-WT ccRCC to PARP inhibition.
- Targeting SLFN11 presents a potential therapeutic strategy for kidney cancers.
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