Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma.

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.

• Authors: Raelene Endersby, Jacqueline Whitehouse, Allison Pribnow, Mani Kuchibhotla, Hilary Hii, Brooke Carline, Suresh Gande, Jennifer Stripay, Mathew Ancliffe, Meegan Howlett, Tobias Schoep, Courtney George, Clara Andradas, Patrick Dyer, Marjolein Schluck, Brett Patterson, Silvia K Tacheva-Gigorova, Matthew N Cooper, Giles Robinson, Clinton Stewart, Stefan M Pfister, Marcel Kool, Till Milde, Amar Gajjar, Terrance Johns, Robert J Wechsler-Reya, Martine F Roussel, Nicholas G Gottardo
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 577 (01 20 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 33472956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Protein Kinase Inhibitors
• DNA

Topics

• Animals
• Cell Cycle
• Cell Cycle Checkpoints
• Cell Line, Tumor
• Cerebellar Neoplasms
• DNA
• Humans
• Medulloblastoma (drug therapy)
• Mice
• Protein Kinase Inhibitors (pharmacology, therapeutic use)