Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma
Shivendra Singh1, Ahmed Abu-Zaid1, Hongjian Jin2
1Department of Surgery, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Abstract:
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1+ RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.
Insights
Histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability in alveolar rhabdomyosarcoma (RMS). Inhibiting KDM4B targets the PAX3-FOXO1 fusion protein network, offering a new treatment strategy for this aggressive childhood cancer.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Chimeric transcription factors, like PAX3-FOXO1 in alveolar rhabdomyosarcoma (RMS), drive oncogenesis but are challenging therapeutic targets.
- PAX3-FOXO1 is the defining fusion protein in RMS, controlling a critical network of transcription factors essential for tumor maintenance.
Purpose of the Study:
- To identify and validate therapeutic vulnerabilities in PAX3-FOXO1-positive (PAX3-FOXO1+) alveolar RMS.
- To investigate the role of histone lysine demethylase 4B (KDM4B) as a potential therapeutic target in RMS.
Main Methods:
- Genetic and pharmacologic inhibition of KDM4B in preclinical RMS models.
- Analysis of gene expression changes, focusing on core oncogenic transcription factors.
- Epigenetic profiling of PAX3-FOXO1-regulated superenhancers.
- Combination therapy studies involving KDM4 inhibition and cytotoxic chemotherapy.
Main Results:
- Inhibition of KDM4B significantly delayed tumor growth in PAX3-FOXO1+ RMS models.
- Suppression of KDM4 proteins reduced the expression of key oncogenic transcription factors.
- KDM4 inhibition led to epigenetic modifications within PAX3-FOXO1-governed superenhancers.
- Combined KDM4 inhibition and chemotherapy resulted in tumor regression in xenograft models.
Conclusions:
- KDM4B represents a targetable vulnerability in PAX3-FOXO1+ alveolar RMS.
- Targeting KDM4B disrupts the essential transcription factor network maintained by PAX3-FOXO1.
- This finding suggests a promising therapeutic strategy for fusion-positive RMS.
