Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma
- 20 January 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 13 (577)
- https://doi.org/10.1126/scitranslmed.aba7401
Abstract
Medulloblastoma (MB) consists of four core molecular subgroups with distinct clinical features and prognoses. Treatment consists of surgery, followed by radiotherapy and cytotoxic chemotherapy. Despite this intensive approach, outcome remains dismal for patients with certain subtypes of MB, namely, MYC-amplified Group 3 and TP53-mutated SHH. Using high-throughput assays, six human MB cell lines were screened against a library of 3208 unique compounds. We identified 45 effective compounds from the screen and found that cell cycle checkpoint kinase (CHK1/2) inhibition synergistically enhanced the cytotoxic activity of clinically used chemotherapeutics cyclophosphamide, cisplatin, and gemcitabine. To identify the best-in-class inhibitor, multiple CHK1/2 inhibitors were assessed in mice bearing intracranial MB. When combined with DNA-damaging chemotherapeutics, CHK1/2 inhibition reduced tumor burden and increased survival of animals with high-risk MB, across multiple different models. In total, we tested 14 different models, representing distinct MB subgroups, and data were validated in three independent laboratories. Pharmacodynamics studies confirmed central nervous system penetration. In mice, combination treatment significantly increased DNA damage and apoptosis compared to chemotherapy alone, and studies with cultured cells showed that CHK inhibition disrupted chemotherapy-induced cell cycle arrest. Our findings indicated CHK1/2 inhibition, specifically with LY2606368 (prexasertib), has strong chemosensitizing activity in MB that warrants further clinical investigation. Moreover, these data demonstrated that we developed a robust and collaborative preclinical assessment platform that can be used to identify potentially effective new therapies for clinical evaluation for pediatric MB.Keywords
Funding Information
- National Cancer Institute (CA-09832)
- National Cancer Institute (CA-02165)
- National Cancer Institute (CA159859)
- National Cancer Institute (CA30199)
- American Lebanese Syrian Associated Charities
- National Health and Medical Research Council
- William’s Superhero Fund
- McDowell Charity Trust
- Innovative Medicines Initiative (116064)
- The Pirate Ship Foundation
- The Kids Cancer Project
- Perth Children’s Hospital Foundation
- Cancer Australia (1101390)
- Cancer Australia (1147153)
- Cancer Council Western Australia (1129386)
- Cure Brain Cancer Foundation
- Telethon-Perth Children’s Hospital Research Fund
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