Dual Inhibition of DNA methylation and PARP Increases Anti-tumor Efficacy in SETD2 Deficient Kidney Cancer

ABSTRACT: Purpose: SETD2 deficiency, a driving force of depleted levels of H3K36me3 due to impaired methyltransferase activity, plays an important role in diverse forms of cancer, most notably in aggressive and metastatic clear cell renal cell carcinomas (ccRCC). Developing novel treatment schema targeting SETD2-compromised cancer cells are urgently needed. Methods: Human kidney cancer cell lines with or without SETD2 deficiency were treated with a DNA Hypomethylating Agent (HMA), a poly(ADP-ribose) polymerase inhibitor (PARPi), and both (HMA + PARPi) in combination in both in vitro and in vivo settings. Cell inhibition, Comet, flow cytometry, western blot, and RNA-sequencing (RNA-seq) gene expression assays as well as bioinformatic analyses were performed to explore the underlying mechanism action. Results: By taking advantage of involvement of SETD2 in DNA methylation and DNA repair, we found the combination treatment of an HMA (5-Aza-CdR/DAC) and a PARPi (Talazoparib/BMN-673) generated increased cytotoxicity in in vitro SETD2-deficient RCC cell lines than in SETD2-proficient cell lines. Furthermore, our results also demonstrate synergetic anti-tumor effects in SETD2 deficiency RCC cell lines when treated with DAC and BMN-673 that include apoptotic induction, increased DNA damage, insufficient DNA damage repair, upregulation of immune responses by STING and transposable elements (TEs), as well as increased genomic instability. Finally, the combination treatment for SETD2-deficient RCCs was also validated using in vivo mouse models. Conclusion: SETD2 deficiency creates a vulnerable epigenetic status to generate efficacious anti-tumor effects via the combination treatment of DAC and BMN-673 in human and mouse RCC systems, making it a precise medicine-based approach for SETD2-compromised cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223893 | GEO | 2023/08/29

REPOSITORIES: GEO