Exploiting Primed Inflammatory Signaling to Target SETD2 Deficient Renal Tumors

Renal cell carcinoma (RCC) is a prototype for the study of epigenetic regulators as major drivers of the cancer phenotype. It is also a notable as a cancer with few effective treatment options, and high degree resistance to many traditional therapies. One important discovery in this cancer is high frequency mutation of SETD2, a histone methyltransferase that is the sole enzyme responsible for placing the histone H3 lysine 36 trimethylation (H3K36me3) mark on actively transcribed genes. We recently made the exciting discovery that SETD2 deficient RCC cells are exquisitely sensitive A1331852, a selective inhibitor for the antiapoptotic BCL-XL protein. Interestingly, we find SETD2 deficiency primes inflammatory signaling and alters cell cycle progression in RCC cells. BCL-XL inhibition further agonizes inflammatory signaling and induces lethal cell cycle transit that culminates in RCC cell death. We show that the activation CGAS-STING pathway is necessary for primed inflammatory signaling and sensitivity BCL-XL inhibition. The CGAS-STING pathway is key to initiating inflammatory signaling in response to certain cytoplasmic DNAs. Our data shows that loss of SETD2 alters mitochondrial dynamics to promote mtDNA leakage, which activates CGAS-STING in these cells. In addition to its antiapoptotic function, BCL-XL is known to delay cell cycle entry and progression. We show that cell cycle transit is necessary for BCL-XL inhibitor-induced cell death in SETD2 deficient cells. This agonizes CGAS-STING to further increase tumor cell-intrinsic inflammatory signaling. Activated inflammatory signaling can increase tumoral immunogenicity and shape the tumor microenvironment (TME) to be more amenable to immune checkpoint inhibitors (ICI). Given the link between tumor-intrinsic inflammation and response to ICIs in RCC, these data open the door for considering SETD2's contribution to RCC progression and treatment in a completely new way via inflammatory signaling via altered mitochondrial dynamics. Based on these data, we hypothesize that altered mitochondrial dynamics promotes mtDNA leakage and primes inflammatory signaling that creates a dependency on BCL-XL, and that this primed inflammatory signaling, in combination with targeting BCL-XL, provides an opportunity to improve response to ICI in SETD2 deficient RCCs. We are proposing a multifaceted collaborative project to: 1) Elucidate the mechanism governing leakage of mitochondrial DNA in SETD2-deficient cells. 2) Establish the role of BCL-XL in cell cycle progression in SETD2- deficient cells, and 3) Determine the extent that SETD2-deficient tumor microenvironment impacts immune cell function. We believe that our studies are innovative and will provide a clear understanding of kidney cancer- intrinsic and -extrinsic inflammatory signaling, related to SETD2 deficiency, contributes to tumor development, progression and response to chemo/immunotherapy. Project Number: 1R01CA300719-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Aguirre de Cubas | Institution: MEDICAL UNIVERSITY OF SOUTH CAROLINA, CHARLESTON, SC | Award Amount: $616,624 | Activity Code: R01 | Study Section: Tumor Host Interactions Study Section[THI] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298002