Targeting the replication stress response in cancer

Pharmacol Ther. 2018 Aug;188:155-167. doi: 10.1016/j.pharmthera.2018.03.005. Epub 2018 Mar 24.

Abstract

Many conventional chemotherapies used in cancer treatment exert their effect by inflicting DNA damage. Highly proliferative tissues, as well as tumour cells, are particularly vulnerable to this damage resulting in unwanted toxicities. In contrast, a targeted therapeutic approach has the aim of specifically eliminating cancer cells but with a reduced effect on healthy tissue. New therapies have been developed that target the replication stress response (RSR), a branch of the broader DNA damage response that specifically deals with interferences of the normal DNA replication program. Different pharmaceutical companies have developed inhibitors of the RSR kinases ATR, CHK1 and WEE1, which are currently at different phases of clinical development. Here, we review how the RSR works at the molecular level, what is the rationale for its targeting, and how we envisage its best use in the clinic, based on patient selection and combination therapies supported by in vitro and in vivo preclinical studies.

Keywords: ATR; CHK1; Cancer; DNA damage checkpoint response; Replication stress; WEE1.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / antagonists & inhibitors
  • Checkpoint Kinase 1 / antagonists & inhibitors
  • DNA Damage
  • DNA Replication / drug effects*
  • Humans
  • Molecular Targeted Therapy / methods*
  • Neoplasms / drug therapy*
  • Nuclear Proteins / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Checkpoint Kinase 1