Pharmacological targeting the ATR-CHK1-WEE1 axis involves balancing cell growth stimulation and apoptosis.

Joyce P.Y Mak,Hoi Tang Ma,Wing Yu Man,Randy Y.C Poon

doi:10.18632/oncotarget.2508

Joyce P.Y Mak, Hoi Tang Ma + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.2508

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Journal: Oncotarget	Publication Date: Sep 25, 2014
Citations: 54	License type: cc-by

Affiliation: Hong Kong University of Science and Technology

Abstract

The ATR-CHK1-WEE1 kinase cascade's functions in the DNA damage checkpoints are well established. Moreover, its roles in the unperturbed cell cycle are also increasingly being recognized. In this connection, a number of small-molecule inhibitors of ATR, CHK1, and WEE1 are being evaluated in clinical trials. Understanding precisely how cells respond to different concentrations of inhibitors is therefore of paramount importance and has broad clinical implications. Here we present evidence that in the absence of DNA damage, pharmacological inactivation of ATR was less effective in inducing mitotic catastrophe than inhibition of WEE1 and CHK1. Small-molecule inhibitors of CHK1 (AZD7762) or WEE1 (MK-1775) induced mitotic catastrophe, as characterized by dephosphorylation of CDK1(Tyr15), phosphorylation of histone H39(Ser10), and apoptosis. Unexpectedly, partial inhibition of WEE1 and CHK1 had the opposite effect of accelerating the cell cycle without inducing apoptosis, thereby increasing the overall cell proliferation. This was also corroborated by the finding that cell proliferation was enhanced by kinase-inactive versions of WEE1. We demonstrated that these potential limitations of the inhibitors could be overcome by targeting more than one components of the ATR-CHK1-WEE1 simultaneously. These observations reveal insights into the complex responses to pharmacological inactivation of the ATR-CHK1-WEE1 axis.

Highlights

Cyclin-dependent kinase 1 (CDK1) is the major kinase for driving cells into mitosis
We demonstrated that combinatorial treatment of inhibitors targeting the ATR–CHK1–WEE1 pathway may be an alternative and effective strategy in inducing mitotic catastrophe without using DNA damage
A major focus of the clinical development of inhibitors of the ATR–CHK1–WEE1 pathway is for combination with chemo- and radiotherapy

Summary

Introduction

Cyclin-dependent kinase 1 (CDK1) is the major kinase for driving cells into mitosis. A defining characteristic of CDK1 activation is a system of feedback loops that converts the progressive accumulation of its activating partner cyclin B1 into an abrupt activation of CDK1 [1]. Premature activation of cyclin B1–CDK1 complexes is prevented by a mechanism involving inhibitory phosphorylation of CDK1Thr14/Tyr by MYT1 and WEE1. At the end of G2, the stockpile of inactive cyclin B1–CDK1 complexes is rapidly activated by CDC25 phosphatases. Cyclin B1–CDK1 catalyzes its own activation with feedback loops that activate CDC25 and inactivate WEE1/MYT1. MYT1, a kinase that normally bound to the endoplasmic reticulum and Golgi complex, can phosphorylate both the Thr and Tyr15 [3,4]. While WEE1 plays an indispensable role in controlling the timing of mitosis, MYT1 appears to play a relatively minor role in the somatic cell cycle [5]

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