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Ref Type Journal Article
PMID (20024691)
Authors Riesterer O, Matsumoto F, Wang L, Pickett J, Molkentine D, Giri U, Milas L, Raju U
Title A novel Chk inhibitor, XL-844, increases human cancer cell radiosensitivity through promotion of mitotic catastrophe.
Journal Investigational new drugs
Vol 29
Issue 3
Date 2011 Jun
URL
Abstract Text Check point kinases (Chk) play a major role in facilitating DNA repair upon radiation exposure. We tested the potency of a novel inhibitor of Chk1 and Chk2, XL-844 (provided by Exelixis Inc., CA, USA), to radiosensitize human cancer cells grown in culture and investigated the underlying mechanisms. HT-29 cells (a human colon cancer line) were exposed to XL-844, radiation, or both, and assessed for clonogenic cell survival. Treatment-dependent effects on phosphorylated forms of Chk proteins were assessed by Western blots. Further mechanistic investigations in HT-29 cells included cell cycle analysis by flowcytometry and assessment of DNA repair kinetics by immuno-cytochemistry (ICC) for nuclear appearance of the phosphorylated form of histone 2AX protein (γ-H2AX) staining. Cells undergoing mitotic catastrophe were identified by irregular pattern of mitotic spindle markers α and γ-tubulin staining by ICC. XL-844 enhanced radiosensitivity in a dose and schedule-dependent manner and the enhancement factor was 1.42 at 0.5 survival fraction. Mechanistically XL-844 abrogated radiation-induced Chk2 phosphorylation, induced pan-nuclear γ-H2AX, and prolonged the presence of radiation-induced γ-H2AX foci, and promoted mitotic catastrophe. In conclusion, our data showed that inhibition of Chk2 activity by XL-844 enhanced cancer cell radiosensitivity that was associated with inhibition of DNA repair and induction of mitotic 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
XL-844 XL-844 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
XL-844 CHK Inhibitor (Pan) 2 XL-884 is CHK1 and CHK2 inhibitor, which may enhance radiosensitivity of tumor cells (PMID: 20024691).
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 colon carcinoma not applicable Radiotherapy + XL-844 Preclinical - Cell culture Actionable In a preclinical study, radiation effects were enhanced by the addition of XL-844 in colon carcinoma cells in culture, demonstrating inhibition of DNA repair, mitotic catastrophe, and decreased cell survival (PMID: 20024691). 20024691