Therapeutic Vulnerability of SETD2 Mutant RCC
Abstract
Clear cell renal cell carcinoma (RCC) is the most common form of kidney cancer and individual tumors exhibit extensive intratumor genetic heterogeneity. A major driver of this heterogeneity is loss of the tumor suppressor SETD2, which also contributes to worse progression free survival and metastasis. The goal of this project is to determine therapeutic vulnerabilities of cells and tumors lacking SETD2, namely Rigosertib, a Polo-like kinase inhibitor. Our previous work here identified that Rigosertib will not be efficacious in vivo as its activity is inhibited by a physiological waste product called uric acid (UA), which is present in serum and even higher in renal tissues and tumors. This work is currently under review at Journal of Clinical Investigation. We subsequently identified an orthogonal compound (ON-1500) that functions similarly to Rigosertib but is more potent, but we have made little progress with this compound due to availability issues. During these experiments, we identified loss of SETD2 or its catlytic activity leads to formation of isochromosomes, or chromosomes that are mirror images of themselves. We also identified that the activity of RAD52 drives these chromosomal alterations, and this work has been recently accepted at PNAS. Future work will determine whether RAD52 and SETD2 loss are synthetically lethal and/or decrease intratumoral heterogeneity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2023
- Accession Number
- AD1217441
Entities
People
- Frank Mason
Organizations
- Vanderbilt University Medical Center