Histone chaperone FACT complex inhibitor CBL0137 interferes with DNA damage repair and enhances sensitivity of medulloblastoma to chemotherapy and radiation.

Abstract

Medulloblastoma (MB) is a malignant pediatric brain tumor with a poor prognosis. Post-surgical radiation and cisplatin-based chemotherapy have been a mainstay of treatment, which often leads to substantial neurocognitive impairments and morbidity, highlighting the need for a novel therapeutic target to enhance the sensitivity of MB tumors to cytotoxic therapies. We performed a comprehensive study using a cohort of 71 MB patients' samples and pediatric MB cell lines and found that MB tumors have elevated levels of nucleosome remodeling FACT (FAcilitates Chromatin Transcription) complex and DNA repair enzyme AP-endonuclease1 (APE1). FACT interacts with APE1 and facilitates recruitment and acetylation of APE1 to promote repair of radiation and cisplatin-induced DNA damage. Further, levels of FACT and acetylated APE1 both are correlate strongly with MB patients' survival. Targeting FACT complex with CBL0137 inhibits DNA repair and alters expression of a subset of genes, and significantly improves the potency of cisplatin and radiation in vitro and in MB xenograft. Notably, combination of CBL0137 and cisplatin significantly suppressed MB tumor growth in an intracranial orthotopic xenograft model. We conclude that FACT complex promotes chemo-radiation resistance in MB, and FACT inhibitor CBL0137 can be used as a chemo-radiation sensitizer to augment treatment efficacy and reduce therapy-related toxicity in high-risk pediatric patients.

• Authors: Heyu Song, Shaoyan Xi, Yingling Chen, Suravi Pramanik, Jiping Zeng, Shrabasti Roychoudhury, Hannah Harris, Anum Akbar, Salma S Elhag, Donald W Coulter, Sutapa Ray, Kishor K Bhakat
• Journal: Cancer letters (Cancer Lett) Vol. 520 Pg. 201-212 (11 01 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 34271103 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• CBLC137
• Carbazoles
• DNA-Binding Proteins
• High Mobility Group Proteins
• Histone Chaperones
• SSRP1 protein, human
• Transcriptional Elongation Factors
• APEX1 protein, human
• DNA-(Apurinic or Apyrimidinic Site) Lyase
• Cisplatin

Topics

• Adolescent
• Adult
• Animals
• Carbazoles (administration & dosage, adverse effects)
• Child
• Child, Preschool
• Cisplatin (administration & dosage, adverse effects)
• DNA Damage (drug effects, radiation effects)
• DNA Repair (drug effects, radiation effects)
• DNA-(Apurinic or Apyrimidinic Site) Lyase (genetics)
• DNA-Binding Proteins (antagonists & inhibitors, genetics)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
• Heterografts
• High Mobility Group Proteins (antagonists & inhibitors, genetics)
• Histone Chaperones (genetics)
• Humans
• Male
• Medulloblastoma (drug therapy, genetics, pathology, radiotherapy)
• Mice
• Transcriptional Elongation Factors (antagonists & inhibitors, genetics)
• Young Adult