Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy

被引:153
作者
Guertin, Amy D. [1 ]
Li, Jing [2 ]
Liu, Yaping [2 ]
Hurd, Melissa S. [1 ]
Schuller, Alwin G. [1 ]
Long, Brian [1 ]
Hirsch, Heather A. [1 ]
Feldman, Igor [1 ]
Benita, Yair [1 ]
Toniatti, Carlo [1 ]
Zawel, Leigh [1 ]
Fawell, Stephen E. [1 ]
Gilliland, D. Gary [1 ]
Shumway, Stuart D. [1 ]
机构
[1] Merck Res Labs, Boston, MA 02115 USA
[2] Merck Res Labs, N Wales, PA USA
关键词
CYCLIN-DEPENDENT KINASES; GENE-EXPRESSION; CANCER-CELLS; ANTITUMOR-ACTIVITY; GROWTH-INHIBITION; GENOME INTEGRITY; IN-VITRO; CHK1; PHOSPHORYLATION; IDENTIFICATION;
D O I
10.1158/1535-7163.MCT-13-0025
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 EC50 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, gamma H2AX 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. (C)2013 AACR.
引用
收藏
页码:1442 / 1452
页数:11
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