Molecular Pathways: Targeting ATR in Cancer Therapy

Abstract

The human ATR gene encodes a kinase that is activated by DNA damage and replication stress as a central transducer of a checkpoint signaling pathway. Once activated, ATR phosphorylates multiple substrates, including the kinase Chk1, to regulate cell cycle progression, replication fork stability, and DNA repair. These events promote cell survival during replication stress and in cells with DNA damage. Accordingly, there has been the tantalizing possibility that ATR inhibitors would be therapeutically useful, especially if they were more effective in tumor versus normal cells. Indeed, multiple studies have demonstrated that alterations that promote tumorigenesis, such as defects in the ATM-p53 pathway, constitutive oncogene activation, and acquisition of the alternative lengthening of telomeres pathway, render tumor cells sensitive to ATR inhibitor monotherapy and/or increase the synergy between ATR inhibitors and genotoxic chemotherapies. Now, nearly two decades after the discovery of ATR, two highly selective and potent ATR inhibitors, AZD6738 and VX-970, are in early phase clinical trials either as monotherapies or paired with a variety of genotoxic chemotherapies. These trials will generate important insights into the effects of ATR inhibition in humans and the potential role of inhibiting this kinase in the treatment of human malignancies.

DNA damage-induced ATM- and Rad-3-related (ATR) kinase activation in non-replicating cells is regulated by the XPB subunit of transcription factor IIH (TFIIH)

“…These findings are also relevant to the use of ATR kinase inhibitors in cancer chemotherapy regimens (7,8,10). In addition to facilitating cell death of rapidly proliferating cancer cells, the results suggest that ATR inhibitors may provide protection to other cell types that are not actively undergoing DNA synthesis.…”

“…These pro-survival functions of ATR in cells containing replication stress likely limit the therapeutic efficacy of anti-cancer drugs that damage DNA, and thus small molecule inhibitors of the ATR kinase are being developed as adjuvants in chemotherapy regimens (7)(8)(9)(10).…”

Suppression of p16 induces mTORC1-mediated nucleotide metabolic reprogramming

“…Although robust ATR activation leads to S-phase or G2 arrest (Gaillard et al, 2015;Liu et al, 2007), mild activation facilitates transformation (Lopez-Contreras et al, 2012). Consistently, ATR signaling is often critical for cancer cell survival (Karnitz and Zou, 2015;Weber and Ryan, 2015), likely due to the ability of ATR signaling to mitigate the increased replication stress that occurs in cancer cells (Zeman and Cimprich, 2014).…”

Dissociation of gemcitabine chemosensitization by CHK1 inhibition from cell cycle checkpoint abrogation and aberrant mitotic entry

“…Indeed, CHK1 inhibitors have played a critical role in establishing the potential of the general strategy of targeting DNA damage response pathways for cancer therapy and newer CHK1 inhibitors are in development. 16 This field has grown considerably in the last decade with the introduction of many agents designed to target other proteins in the DNA replication, DNA repair, and cell cycle checkpoint pathways such as ATR, 40 RPA 41 and WEE1. 32,42 Given the lack of effective strategies to treat pancreatic cancer, and the demonstrated efficacy of CHK1 inhibitors in sensitizing pancreatic cancers to gemcitabine or gemcitabine-based chemoradiation, 13,20,27,28 second generation CHK1 inhibitors or other agents which target these pathways should continue to be explored as potential therapeutic options.…”