DNA replication stress as an Achilles' heel of cancer

Comment on: Constitutive activation of DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lym-phoma. Derenzini et al. There is now significant evidence indicating that replication stress (RS) is prevalent in human cancers and that it is induced by the constitutively activated oncogenes that are driving cancer cell proliferation [1]. The collapsed replication forks and DNA damage associated with RS are most likely a significant driver of the genomic instability present in human cancers. At the same time, DNA damage activates the p53 tumor suppressor protein, which induces senescence or apoptosis. Thus, RS provides a selective advantage to inactivate p53, thereby explaining the high frequency of p53 mutations in human cancers. Supporting this sequence of events, RS is evident in precancerous lesions before overt genomic rearrangements and p53 mutations [1]. RS is also likely to affect the response of cancer cells to therapy. Indeed, most of the empirically identified cancer therapies that are used today as first-line therapy have some connection to RS. For example, gemcitabine and cytarabine are deoxycytidine analogs; camptothecin, etoposide and adriamycin (doxorubicin) are topoisomerase inhibitors; and alkylating agents, cisplatin and irradiation induce DNA lesions, which stop or impede fork progression. The efficacy of these agents could reflect the high proliferation rate of cancer cells. However, the presence of RS in cancers could also be important, as cancer cells already have " difficulty " replicating their genomes and are, therefore, more sensitive to the treatment than normal cells. A recent study supports the above argument. The degree of RS in a cohort of diffuse large B-cell lymphomas (DLBCLs) correlated to survival of patients treated with standard therapies [2]. This correlation held even when patients with similar international prognostic indices were compared. A previous study examining patients with early operable non-small cell lung cancer reported similar findings [3]. RS may not only serve as a prognostic indicator, but, perhaps could also be exploited for development of more effective therapies. Both checkpoint and repair pathways are activated in response to RS. The RS checkpoint is mediated by the kinase ATR, which phosphorylates and activates the kinase Chk1; in turn, Chk1 inhibits cell cycle progression. ATR and Chk1 inhibitors are at various stages of preclinical and clinical testing. ATR inhibitors potentiate RS and exhibit synthetic lethality with cancer-associated mutations in tissue culture cell systems. In the clinic, phase I studies are underway to assess their safety …