Reference Detail

Ref Type

Journal Article

PMID

(26141948)

Authors

King C, Diaz HB, McNeely S, Barnard D, Dempsey J, Blosser W, Beckmann R, Barda D, Marshall MS

Title

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	9	2015 Sep	2004-13	Mol Cancer Ther

URL

Abstract Text

CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Cytarabine + Etoposide + Mitoxantrone + Prexasertib	Cytarabine Etoposide Mitoxantrone Prexasertib	0	1
Prexasertib	Prexasertib	1	8

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Prexasertib		LY2606368\|IC-83\|ACR-368\|ACR368\|ACR 368	CHK1 Inhibitor 18	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
CHEK1 positive	lung non-small cell carcinoma	predicted - sensitive	Prexasertib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Prexasertib (LY2606368) increased apoptosis of non-small cell lung cancer (NSCLC) cells in culture, and inhibited Chek1 phosphorylation, induced DNA damage, and reduced tumor growth in a NSCLC cell line xenograft model (PMID: 26141948).	26141948