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

来源：

MOLECULAR CANCER THERAPEUTICS | 2013年 / 12卷 / 08期

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

页码：1442 / 1452

页数：11

共 43 条

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