Targeting DNA Replication Stress for Cancer Therapy

Abstract

The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR) mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress.

DNA replication stress and cancer chemotherapy

“…Molecular targeting drugs that modulate DDR in response to DRS are expected to have antitumor effects. Indeed, several kinase inhibitors against ATR or Chk1 are currently under investigation in clinical trials as anticancer drugs . We anticipate that even low doses of these drugs would significantly enhance the anticancer effect of chemotherapeutic drugs that trigger DRS.…”

Perturbations in the Replication Program Contribute to Genomic Instability in Cancer

“…Inhibitors of the DDR are useful targets in cancer therapy as their inhibition will speed up mitotic catastrophe (reviewed in [106,107]). Several Chk1 and ATR inhibitors are in clinical trials for anticancer therapy.…”

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

“…DNA damage response (DDR) deficiency is a hallmark of cancer, including PC 8 , which is thought to render some tumors preferentially sensitive to DNA damaging agents such as platinum. There is a growing compendium of novel therapeutics that target DNA damage response mechanisms and the cell cycle such as ATR and WEE1 inhibitors 21 . Genomic instability, a key feature of many cancers, typically secondary to defects in DNA replication and repair during the cell cycle often results in replication stress 22,23 .…”