Directing the use of DDR kinase inhibitors in cancer treatment

ABSTRACT

Introduction: Defects in the DNA damage response (DDR) drive the development of cancer by fostering DNA mutation but also provide cancer-specific vulnerabilities that can be exploited therapeutically. The recent approval of three different PARP inhibitors for the treatment of ovarian cancer provides the impetus for further developing targeted inhibitors of many of the kinases involved in the DDR, including inhibitors of ATR, ATM, CHEK1, CHEK2, DNAPK and WEE1.

Areas covered: We summarise the current stage of development of these novel DDR kinase inhibitors, and describe which predictive biomarkers might be exploited to direct their clinical use.

Expert opinion: Novel DDR inhibitors present promising candidates in cancer treatment and have the potential to elicit synthetic lethal effects. In order to fully exploit their potential and maximize their utility, identifying highly penetrant predictive biomarkers of single agent and combinatorial DDR inhibitor sensitivity are critical. Identifying the optimal drug combination regimens that could used with DDR inhibitors is also a key objective.

KEYWORDS:

• Cancer
• cell cycle
• DNA damage response (DDR)
• kinase inhibitors
• replication stress

Article highlights

• Inhibitors of the DDR kinases ATM, ATR, DNA-PK, CHK1, CHK2 and WEE1 are now being assessed in phase I and phase II clinical trials for the treatment of cancer.

• These novel DDR inhibitors (DDRi) have the potential to exploit synthetic lethal interactions that operate in tumour cells, as well as exploiting other commonly found hallmarks of cancer, including genomic instability and replication fork stress

• Pre-clinical studies have identified a series of candidate predictive biomarkers of sensitivity to DDRi, some of which are suitable for assessment in clinical trials.

• Thus far, few mechanisms of DDRi resistance have been identified, although such effects seem likely

• Drug combination strategies might be used to enhance the overall effectiveness of DDRi, but as for single agent DDRi use, predictive biomarkers are required to direct the use of combination approaches

This box summarizes key points contained in the article.

Acknowledgments

We thank Breast Cancer Now and Cancer Research UK for funding the work in our laboratory and their continued support.

Declaration of Interest

C. J. Lord and C. Williamson are inventors on patents describing the use of DDR inhibitors in cancer and stand to gain for their use as part of the ICR ‘Rewards to Inventors’ scheme. C. J. Lord receives/has received research funding from Merck KGaA, Vertex and Astra Zeneca. E. D. G. Fleuren is the recipient of a Rubicon Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was funded by Breast Cancer Now and Cancer Research UK. EDGF is the recipient of a Rubicon Fellowship.