Mutations in KDM6A have been identified as a regulator of therapeutic responses in advanced bladder cancer, sensitizing tumors to anti–PD-1 immune checkpoint inhibition but resisting cisplatin chemotherapy, according to early research published in Nature Communications. Based on this and further research, KDM6A mutations may become a biomarker for guiding treatment selection in advanced bladder cancer.
“Our goal is to move beyond one-size-fits-all treatments,” said corresponding study author Sangeeta Goswami, MD, PhD, Associate Professor of Genitourinary Medical Oncology and Assistant Member of the James P. Allison Institute at The University of Texas MD Anderson Cancer Center. “KDM6A gives us a clinically actionable signal and one that may spare patients from ineffective treatment and improve outcomes.”
Background and Study Methods
Loss-of-function mutations in KDM6A can be found in approximately 26% of advanced bladder cancer cases. Researchers wanted to explore these mutations' impact on therapeutic responses. The study authors looked at CRISPR-Cas9-engineered murine and human bladder cancer models to determine how KDM6A mutations may impact patients' responses to therapy.
Key Findings
The researchers found that KDM6A mutations were associated with poor survival after receipt of cisplatin chemotherapy, but improved outcomes after receipt of anti–PD-1 therapy in advanced bladder cancer.
They found that deficiency in KDM6A leads to more extrachromosomal circular DNA being formed, which carry a chemoresistance loci. On the other hand, KDM6A loss damages the DNA's ability to repair and rewires the tumor metabolism, leading to reduced glucose transformation and lactate output. Histone lactylation is also reduced in regulatory T cells, which suppresses immunoregulatory genes and the expansion of PD-1 regulatory T cells. This finding aligned with prior research from Dr. Goswami's laboratory about the role of histone lactylation in the function of CD8-positive T cells.
“This dual effect—resistance to chemotherapy but heightened responsiveness to immunotherapy—helps explain previously conflicting clinical outcomes,” Dr. Goswami said. The authors added that "Collectively, our findings establish KDM6A mutation as a key regulator of therapeutic responses, providing a foundation for its use in guiding precision therapy in advanced bladder cancer."
DISCLOSURE: This research was supported by the James P. Allison Institute Assistant Member Fund, the MD Anderson Physician Scientist Award, and the National Institutes of Health. For full disclosures of the study authors, visit nature.com.
