ATR/CHK1 inhibitors and cancer therapy

Abstract

The cell cycle checkpoint proteins ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) and its major downstream effector checkpoint kinase 1 (CHK1) prevent the entry of cells with damaged or incompletely replicated DNA into mitosis when the cells are challenged by DNA damaging agents, such as radiation therapy (RT) or chemotherapeutic drugs, that are the major modalities to treat cancer. This regulation is particularly evident in cells with a defective G1 checkpoint, a common feature of cancer cells, due to p53 mutations. In addition, ATR and/or CHK1 suppress replication stress (RS) by inhibiting excess origin firing, particularly in cells with activated oncogenes. Those functions of ATR/CHK1 make them ideal therapeutic targets. ATR/CHK1 inhibitors have been developed and are currently used either as single agents or paired with radiotherapy or a variety of genotoxic chemotherapies in preclinical and clinical studies. Here, we review the status of the development of ATR and CHK1 inhibitors. We also discuss the potential mechanisms by which ATR and CHK1 inhibition induces cell killing in the presence or absence of exogenous DNA damaging agents, such as RT and chemotherapeutic agents. Lastly, we discuss synthetic lethality interactions between the inhibition of ATR/CHK1 and defects in other DNA damage response (DDR) pathways/genes.

Keywords: ATR; CHK1; Cell cycle checkpoints; DNA damage response; DNA replication stress; Synthetic lethality.

Fig. 1

Overview of the DNA damage-induced checkpoint pathways. The ATM/CHK2 and ATR/CHK1 pathways are activated by DNA double-strand breaks or by DNA single-strand breaks and replication stress, respectively. Cell cycle checkpoints are induced primarily through p53, CHK2, CHK1 and p38/MK2, which are phosphorylated by ATM and ATR. Activated p53 leads to G1-phase arrest and induces apoptosis. The phosphorylation of CDC25 by CHK2 and CHK1 abolishes the activation of CDKs, thus stopping cell cycle progression either in S-phase or at the boundary of G2/M. Cancer cells deficient in p53 due to mutation or deletion lack the G1 checkpoint and are more dependent on the intra-S and G2/M checkpoints.

Fig. 2

ATR/CHK1 suppresses oncogene-induced RS. Oncogene activation causes replication stress via uncoordinated origin firing, a reduction in licensed replication origins and inappropriate re-licensing of newly replicated DNA. Increased CDK activity leads to not only dysregulated replication initiation but also a deceased number of licensed replication origins, leading to under-replicated DNA. ATR/CHK1 signaling inhibits oncogene-induced replication stress via CDKs. Although it has been demonstrated that ATR/CHK1 suppresses replication stress via inhibition of CDK-induced replication initiation, it is not clear if ATR/CHK1 suppress CDK-mediated regulation of the number of licensed replication origins. CDK signaling suppressed by ATR/CHK1 is presented by gray arrows.

Fig. 3

The potential synthetic lethality interactions with ATR/CHK1 inhibitions. See text for description. The defect in the second pathway is presented by gray arrows.