Reference Detail

Ref Type Journal Article
PMID (23699655)
Authors Guertin AD, Li J, Liu Y, Hurd MS, Schuller AG, Long B, Hirsch HA, Feldman I, Benita Y, Toniatti C, Zawel L, Fawell SE, Gilliland DG, Shumway SD
Title Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy.
Journal Molecular cancer therapeutics
Vol 12
Issue 8
Date 2013 Aug
URL
Abstract Text Inhibition of the DNA damage checkpoint kinase WEE1 potentiates genotoxic chemotherapies by abrogating cell-cycle arrest and proper DNA repair. However, WEE1 is also essential for unperturbed cell division in the absence of extrinsic insult. Here, we investigate the anticancer potential of a WEE1 inhibitor, independent of chemotherapy, and explore a possible cellular context underlying sensitivity to WEE1 inhibition. We show that MK-1775, a potent and selective ATP-competitive inhibitor of WEE1, is cytotoxic across a broad panel of tumor cell lines and induces DNA double-strand breaks. MK-1775-induced DNA damage occurs without added chemotherapy or radiation in S-phase cells and relies on active DNA replication. At tolerated doses, MK-1775 treatment leads to xenograft tumor growth inhibition or regression. To begin addressing potential response markers for MK-1775 monotherapy, we focused on PKMYT1, a kinase functionally related to WEE1. Knockdown of PKMYT1 lowers the EC(50) of MK-1775 by five-fold but has no effect on the cell-based response to other cytotoxic drugs. In addition, knockdown of PKMYT1 increases markers of DNA damage, γH2AX and pCHK1(S345), induced by MK-1775. In a post hoc analysis of 305 cell lines treated with MK-1775, we found that expression of PKMYT1 was below average in 73% of the 33 most sensitive cell lines. Our findings provide rationale for WEE1 inhibition as a potent anticancer therapy independent of a genotoxic partner and suggest that low PKMYT1 expression could serve as an enrichment biomarker for MK-1775 sensitivity.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
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 colorectal cancer not applicable Adavosertib Preclinical - Cell line xenograft Actionable In a preclinical study, MK-1775 inhibited cell proliferation and promoted DNA damage in a human colorectal cancer cell line in culture, and promoted tumor regression in xenograft models (PMID: 23699655). 23699655
Unknown unknown non-small cell lung carcinoma not applicable Adavosertib Preclinical - Cell line xenograft Actionable In a preclinical study, MK-1775 inhibited cell proliferation and promoted DNA damage in human non-small cell lung carcinoma cell lines in culture, and promoted tumor regression in xenograft models (PMID: 23699655). 23699655
Unknown unknown head and neck squamous cell carcinoma not applicable Adavosertib Preclinical Actionable In a preclinical study, MK-1775 inhibited proliferation in various tumor cell lines, including head and neck squamous cell carcinoma cell lines, in culture (PMID: 23699655). 23699655