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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

The poor selectivity of standard cytotoxic chemotherapy regimens causes severe side-effects in patients and reduces the quality of life during treatment. Targeting cancer-specific vulnerabilities can improve response rates, increase overall survival and limit toxic side effects in patients. Oncogene-induced replication stress serves as a tumour specific vulnerability and rationale for the clinical development of inhibitors targeting the DNA damage response (DDR) kinases (CHK1, ATR, ATM and WEE1). CHK1 inhibitors (CHK1i) have served as the pilot compounds in this class and their efficacy in clinical trials as single agents has been disappointing. Initial attempts to combine CHK1i with chemotherapies agents that enhance replication stress (such as gemcitabine) were reported to be excessively toxic. More recently, it has emerged that combining CHK1i with subclinical doses of replication stress inducers is more effective, better tolerated and more compatible with immunotherapies. Here we focus on the lessons learned during the clinical development of CHK1i with the goal of improving the design of future clinical trials utilizing DDR inhibitors to target replication stress in cancer.

Details

Title
Everything in Moderation: Lessons Learned by Exploiting Moderate Replication Stress in Cancer
Author
Nazareth, Deborah 1 ; Jones, Mathew J K 2 ; Gabrielli, Brian 1 

 Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; [email protected] 
 Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; [email protected]; The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia 
First page
1320
Publication year
2019
Publication date
2019
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2547503125
Copyright
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.