Oncotarget

Research Papers:

A subset of cancer cell lines is acutely sensitive to the Chk1 inhibitor MK-8776 as monotherapy due to CDK2 activation in S phase

Nandini Sakurikar, Ruth Thompson, Ryan Montano and Alan Eastman _

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Oncotarget. 2016; 7:1380-1394. https://doi.org/10.18632/oncotarget.6364

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Abstract

Nandini Sakurikar1, Ruth Thompson1, Ryan Montano1 and Alan Eastman1

1 Department of Pharmacology and Toxicology, and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

Correspondence to:

Alan Eastman, email:

Keywords: cell cycle checkpoint, DNA damage response, Chk1, Wee1, CDK2

Received: September 02, 2015 Accepted: November 16, 2015 Published: November 22, 2015

Abstract

DNA damage activates Checkpoint kinase 1 (Chk1) to halt cell cycle progression thereby preventing further DNA replication and mitosis until the damage has been repaired. Consequently, Chk1 inhibitors have emerged as promising anticancer therapeutics in combination with DNA damaging drugs, but their single agent activity also provides a novel approach that may be particularly effective in a subset of patients. From analysis of a large panel of cell lines, we demonstrate that 15% are very sensitive to the Chk1 inhibitor MK-8776. Upon inhibition of Chk1, sensitive cells rapidly accumulate DNA double-strand breaks in S phase in a CDK2- and cyclin A-dependent manner. In contrast, resistant cells can continue to grow for at least 7 days despite continued inhibition of Chk1. Resistance can be circumvented by inhibiting Wee1 kinase and thereby directly activating CDK2. Hence, sensitivity to Chk1 inhibition is regulated upstream of CDK2 and correlates with accumulation of CDC25A. We conclude that cells poorly tolerate CDK2 activity in S phase and that a major function of Chk1 is to ensure it remains inactive. Indeed, inhibitors of CDK1 and CDK2 arrest cells in G1 or G2, respectively, but do not prevent progression through S phase demonstrating that neither kinase is required for S phase progression. Inappropriate activation of CDK2 in S phase underlies the sensitivity of a subset of cell lines to Chk1 inhibitors, and this may provide a novel therapeutic opportunity for appropriately stratified patients.


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