Multiple DNA damage-dependent and DNA damage-independent stress responses define the outcome of ATR/Chk1 targeting in medulloblastoma cells

Krüger, Katharina; Geist, Katharina; Stuhldreier, Fabian; Schumacher, Lena; Blümel, Lena; Remke, Marc; Wesselborg, Sebastian; Stork, Björn; Klöcker, Nicolaj; Bormann, Stefanie; Roos, Wynand P.; Honnen, Sebastian; Fritz, Gerhard

doi:10.1016/j.canlet.2018.05.011

Cited by 17 publications

(18 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…That study found that drug interactions predicted to be either additive or antagonistic in vitro were antagonistic when evaluated in vivo; thus, we chose to not investigate WEE1, PLK1, or CDK4/6 inhibitors further and instead pursued the clinical potential of CHK inhibitors. In addition to our unbiased screen, several independent studies had previously implicated CHK1 or CHK2 or both as viable targets in MB (45,46). There is promising clinic data emerging for PLK1 and WEE1 inhibitors (21,47); therefore, it remains of value to determine their effectiveness in vivo as MB therapies.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…ATR inhibitors AZ20 and MSC253 also inhibited growth of Ewing sarcoma xenografts (Nieto-Soler et al, 2016), although more modest antitumor activity was reported from the PPTP study, which evaluated the ATR inhibitor M6620 against solid tumor panels, including neuroblastoma . Consistent with the notion that oncogene-induced replicative stress may confer hypersensitivity to Chk1 inhibitors, a medulloblastoma cell line with high c-MYC was reported to be more sensitive than a Sonic Hedgehog subtype cell line (low c-MYC) to the Chk1 inhibitor AZD-7762 (Krüger et al, 2018). An alternative strategy to disrupt cell-cycle checkpoints is to target Wee1 kinase.…”

Section: Exploiting Dna Damage Repair Deficienciesmentioning

confidence: 61%

Challenges and Opportunities for Childhood Cancer Drug Development

Houghton¹,

Kurmasheva²

2019

Pharmacol Rev

View full text Add to dashboard Cite

“…We showed recently that ERKi caused loss of MYC protein, primarily through stimulation of protein degradation (Vaseva et al, 2018). Loss of MYC following CHK1i has been described in RAS WT cancers (Ferrao et al, 2012;Kr€ uger et al, 2018;Ravi et al, 2016). However, as CHK1i elevated ERK activity, which is a driver of MYC protein stability, loss of MYC was not expected in KRAS mutant PDAC.…”

Section: Discussionmentioning

confidence: 99%

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

et al. 2021

View full text Add to dashboard Cite

show abstract

Multiple DNA damage-dependent and DNA damage-independent stress responses define the outcome of ATR/Chk1 targeting in medulloblastoma cells

Cited by 17 publications

References 79 publications

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

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

Challenges and Opportunities for Childhood Cancer Drug Development

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

Contact Info

Product

Resources

About