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. 2013 Aug;12(8):1442-52.
doi: 10.1158/1535-7163.MCT-13-0025. Epub 2013 May 22.

Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy

Amy D Guertin  1 , Jing Li, Yaping Liu, Melissa S Hurd, Alwin G Schuller, Brian Long, Heather A Hirsch, Igor Feldman, Yair Benita, Carlo Toniatti, Leigh Zawel, Stephen E Fawell, D Gary Gilliland, Stuart D Shumway
Affiliations

Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy

Amy D Guertin et al. Mol Cancer Ther. 2013 Aug.

Abstract

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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