SETD2 Deficiency Confers Sensitivity to Dual Inhibition of DNA Methylation and PARP in Kidney Cancer

Area of Science:

• Oncology
• Epigenetics
• Cancer Therapeutics

Background:

• SETD2 deficiency impacts the epigenetic landscape, notably depleting H3K36me3, and is implicated in aggressive clear-cell renal cell carcinomas (ccRCC).
• Targeted treatment strategies for SETD2-compromised cancers, particularly ccRCC, are urgently needed.
• SETD2's role in DNA methylation and repair suggests potential therapeutic vulnerabilities.

Purpose of the Study:

• To investigate the efficacy of combining a DNA hypomethylating agent (HMA) with a PARP inhibitor (PARPi) in SETD2-deficient ccRCC.
• To evaluate the synergistic effects, mechanisms of action, and in vivo efficacy of this combination therapy.

Main Methods:

• Utilized human ccRCC cell lines with and without SETD2 deficiency.
• Administered 5-aza-2'-deoxycytidine (DAC) as the HMA and talazoparib (BMN-673) as the PARPi, both individually and in combination.
• Assessed cytotoxicity, apoptosis, DNA damage, DNA repair capacity, genomic instability, immune responses (STING, viral mimicry), and tumor growth in mouse models.

Main Results:

• The DAC + BMN-673 combination synergistically increased cytotoxicity in SETD2-deficient ccRCC cells, but not in SETD2-proficient cells.
• Combination treatment induced apoptosis, elevated DNA damage, impaired DNA repair, and increased genomic instability.
• Enhanced immune responses, including STING upregulation and transposable element activation, were observed.
• The combination therapy effectively suppressed tumor growth in vivo in SETD2-deficient ccRCC mouse models.

Conclusions:

• Combining HMAs and PARPis represents a promising therapeutic strategy for SETD2-compromised ccRCC.
• This approach targets the epigenetic vulnerability created by SETD2 deficiency.
• The findings support a precision medicine-based strategy for SETD2-compromised cancers.