The cancer therapeutic potential of Chk1 inhibitors: how mechanistic studies impact on clinical trial design

Abstract

Many anticancer agents damage DNA and activate cell cycle checkpoints that permit time for the cells to repair their DNA and recover. These checkpoints have undergone intense investigation as potential therapeutic targets and Chk1 inhibitors have emerged as promising novel therapeutic agents. Chk1 was initially recognized as a regulator of the G2/M checkpoint, but has since been demonstrated to have additional roles in replication fork stability, replication origin firing and homologous recombination. Inhibition of these pathways can dramatically sensitize cells to some antimetabolites. Current clinical trials with Chk1 inhibitors are primarily focusing on their combination with gemcitabine. Here, we discuss the mechanisms of, and emerging uses for Chk1 inhibitors as single agents and in combination with antimetabolites. We also discuss the pharmacodynamic issues that need to be addressed in attaining maximum efficacy in vivo. Following administration of gemcitabine to mice and humans, tumour cells accumulate in S phase for at least 24 h before recovering. In addition, stalled replication forks evolve over time to become more Chk1 dependent. We emphasize the need to assess cell cycle perturbation and Chk1 dependence of tumours in patients administered gemcitabine. These assessments will define the optimum dose and schedule for administration of these drug combinations.

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

“…damaging agents (8). The key role that CHK1 plays in the rapid activation of the S and G 2 -M checkpoints is due to the tight integration of CHK1 into normal DNA replication and DNA damage repair.…”

“…Cell death brought about by this combination of replication failure, DSB generation, and loss of DNA damage checkpoints has been called replication catastrophe (13). A number of CHK1 inhibitors have entered clinic trials, primarily in combination with DNA-damaging agents (7,8). LY2606368 was developed as a second-generation CHK1 inhibitor to have increased potency in vivo and is being assessed clinically both as a single agent (NCT01115790) as well as in combination with cytotoxic and targeted agents (NCT02124148).…”

“…Cytosolic sequestration of CDC25B and CDC25C prevents the activation of CDK1 resulting in cell-cycle arrest at the G 2 -M boundary. A number of CHK1 inhibitors have been developed and entered the clinic as checkpoint inhibitors to increase the efficacy of chemotherapy in patients with p53-mutant cancer (7,8).…”

CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy

“…However, CHK1 inhibitors have not yet been combined with radiotherapy in clinical trials, possibly due to inadequate selectivity and/or unexpected toxicities observed with earlier compounds (25,26). The CHK1 inhibitor CCT244747 is a highly selective, potent, orally active ATP-competitive CHK1 inhibitor previously shown to enhance the activity of several genotoxic agents, including ionizing radiation (13).…”

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

“…16 Chk1 is an essential kinase in governing cell cycle G 1 /S, S, and G 2 /M phase checkpoints and determining cellular responses to DNA damage. [22][23][24][25][26] In contrast to the well-known utility of Chk1 inhibitors in sensitizing tumors to chemotherapy agents, 23,27,28 Chk1 overexpression or downexpression also occurs in some types of tumors, including breast cancer, ovarian cancer, cervical cancer, and neuroblastoma. 22,[29][30][31][32][33] In our study, we found Chk1 mRNA and protein levels were upregulated in colorectal cancer tissues compared with paired normal tissues, and positively correlated with CCNB1 expression.…”