TY - JOUR
T1 - Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors withDNA-damaging chemotherapies in medulloblastoma
AU - Endersby, Raelene
AU - Whitehouse, Jacqueline
AU - Pribnow, Allison
AU - Kuchibhotla, Mani
AU - Hii, Hilary
AU - Carline, Brooke
AU - Gande, Suresh
AU - Stripay, Jennifer
AU - Ancliffe, Mathew
AU - Howlett, Meegan
AU - Schoep, Tobias
AU - George, Courtney
AU - Andradas, Clara
AU - Dyer, Patrick
AU - Schluck, Marjolein
AU - Patterson, Brett
AU - Silvia, K. Tacheva Gigorova
AU - Cooper, Matthew N.
AU - Robinson, Giles
AU - Stewart, Clinton
AU - Pfister, Stefan M.
AU - Kool, Marcel
AU - Milde, Till
AU - Gajjar, Amar
AU - Johns, Terrance
AU - Wechsler-Reya, Robert J.
AU - Roussel, Martine F.
AU - Gottardo, Nicholas G.
N1 - Publisher Copyright:
Copyright © 2021 The Authors.
PY - 2021/1/20
Y1 - 2021/1/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100228700&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aba7401
DO - 10.1126/scitranslmed.aba7401
M3 - Article
C2 - 33472956
AN - SCOPUS:85100228700
SN - 1946-6234
VL - 13
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 577
M1 - eaba7401
ER -