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Ref Type Journal Article
PMID (28270495)
Authors Lowery CD, VanWye AB, Dowless M, Blosser W, Falcon BL, Stewart J, Stephens J, Beckmann RP, Bence Lin A, Stancato LF
Title The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 15
Date 2017 Aug 01
URL
Abstract Text Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G2-M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma.Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma.Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature.Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Drug Name Trade Name Synonyms Drug Classes Drug Description
Prexasertib LY2606368|IC-83 CHK1 Inhibitor 14 Prexasertib (LY2606368) inhibits checkpoint kinase 1 (Chk1), which may result in accumulation of DNA damage and decreased tumor growth (PMID: 26141948, PMID: 28270495, PMID: 32539469, PMID: 32510664).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown osteosarcoma not applicable Prexasertib Preclinical - Cell culture Actionable In a preclinical study, Prexasertib (LY2606368) decreased proliferation of several pediatric tumor cell lines in culture, including osteosarcoma cell lines (PMID: 28270495). 28270495
Unknown unknown neuroblastoma not applicable Prexasertib Preclinical - Cell line xenograft Actionable In a preclinical study, Prexasertib (LY2606368) decreased proliferation and increased apoptosis of neuroblastoma cell lines in culture, and induced tumor regression in neuroblastoma cell line xenograft models (PMID: 28270495). 28270495
Unknown unknown rhabdomyosarcoma not applicable Prexasertib Preclinical - Cell culture Actionable In a preclinical study, Prexasertib (LY2606368) decreased proliferation of several pediatric tumor cell lines in culture, including rhabdomyosarcoma cell lines (PMID: 28270495). 28270495
Unknown unknown retinoblastoma not applicable Prexasertib Preclinical - Cell culture Actionable In a preclinical study, Prexasertib (LY2606368) decreased proliferation of several pediatric tumor cell lines in culture, including a retinoblastoma cell line (PMID: 28270495). 28270495
Unknown unknown acute lymphoblastic leukemia not applicable Prexasertib Preclinical - Cell culture Actionable In a preclinical study, Prexasertib (LY2606368) decreased proliferation of several pediatric tumor cell lines in culture, including acute lymphoblastic leukemia cell lines (PMID: 28270495). 28270495
Unknown unknown medulloblastoma not applicable Prexasertib Preclinical - Cell culture Actionable In a preclinical study, Prexasertib (LY2606368) decreased proliferation of several pediatric tumor cell lines in culture, including medulloblastoma cell lines (PMID: 28270495). 28270495
Unknown unknown neuroblastoma no benefit Doxorubicin + Prexasertib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Adriamycin (doxorubicin) and Prexasertib (LY2606368) did not demonstrate benefit over Prexasertib (LY2606368) alone in neuroblastoma cell line xenograft models (PMID: 28270495). 28270495
Unknown unknown Ewing sarcoma not applicable Prexasertib Preclinical - Cell culture Actionable In a preclinical study, Prexasertib (LY2606368) decreased proliferation of several pediatric tumor cell lines in culture, including Ewing sarcoma cell lines (PMID: 28270495). 28270495