Targeting the DNA Repair Enzyme Polymerase θ in Cancer Therapy

Trends Cancer. 2021 Feb;7(2):98-111. doi: 10.1016/j.trecan.2020.09.007. Epub 2020 Oct 24.

Abstract

Targeted cancer therapies represent a milestone towards personalized treatment as they function via inhibition of cancer-specific alterations. Polymerase θ (POLQ), an error-prone translesion polymerase, also involved in DNA double-strand break (DSB) repair, is often upregulated in cancer. POLQ is synthetic lethal with various DNA repair genes, including known cancer drivers such as BRCA1/2, making it essential in homologous recombination-deficient cancers. Thus, POLQ represents a promising target in cancer therapy and efforts for the development of POLQ inhibitors are actively underway with first clinical trials due to start in 2021. This review summarizes the journey of POLQ from a backup DNA repair enzyme to a promising therapeutic target for cancer treatment.

Keywords: double-strand break repair; polymerase theta-mediated end joining; synthetic lethality; targeted cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded
  • DNA Polymerase theta
  • DNA Repair / drug effects
  • DNA-Directed DNA Polymerase / metabolism*
  • Disease Models, Animal
  • Drug Development / trends*
  • Homologous Recombination / drug effects
  • Humans
  • Mice
  • Molecular Targeted Therapy / methods
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / mortality
  • Nucleic Acid Synthesis Inhibitors / pharmacology*
  • Nucleic Acid Synthesis Inhibitors / therapeutic use
  • Prognosis
  • Synthetic Lethal Mutations / drug effects

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Nucleic Acid Synthesis Inhibitors
  • DNA-Directed DNA Polymerase