title: CHK1 and replicative stress in T-cell leukemia: Can an irreverent tumor suppressor end up playing the oncogene?
abstract: Replicative stress (RS) is a cell-intrinsic phenomenon enhanced by oncogenic transformation. Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair. Taking this knowledge into account, one would predict CHK1 behaves strictly as a tumor suppressor. However, the reality seems far more complex. CHEK1 loss-of-function mutations have not been found in human tumors, and transgenic expression of Chek1 in mice promotes oncogene-induced transformation through RS inhibition. Moreover, CHK1 is overexpressed in various human cancers and CHK1 inhibitors have been developed as sensitizers to enhance the cytotoxicity of DNA damage-inducing chemotherapies. Here, we summarize the literature on the involvement of CHK1 in cancer progression, including our recent observation that CHK1 sustains T-cell acute lymphoblastic leukemia (T-ALL) cell viability. We also debate the importance of identifying patients that could benefit the most from treatment with CHK1 inhibitors, taking T-ALL as a model, and propose possible markers of therapeutic response.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Leonor M
authors.initials: LM
authors.lastname: Sarmento
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal. Electronic address: joao_barata@medicina.ulisboa.pt.
authors.forename: João T
authors.initials: JT
authors.lastname: Barata
mesh_terms: D000818:Animals; D000071877:Checkpoint Kinase 1 / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D016147:Genes, Tumor Suppressor; D006801:Humans; D015458:Leukemia, T-Cell / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D009857:Oncogenes
chemical_list: D000071877:Checkpoint Kinase 1
keywords: ATM; ATR; CHK1; Replicative stress; T-ALL; T-cell acute lymphoblastic leukemia; Targeted therapies