Beyond PARP—POLθ as an anticancer target

Since the discovery that DNA is unstable and prone to decay, targeting DNA repair deficiencies has become a proven and effective strategy in the fight against cancer. Over the past decades, it has become increasingly apparent that selective loss of DNA repair pathways is an early and frequent event in tumorigenesis, occurring in 40 to 50% of many cancer types. Loss of DNA repair likely provides a selective growth advantage to tumor cells as this results in genetic instability and/or enhanced mutation rates, which can drive tumor evolution (1). However, DNA repair-deficient cancers often become critically dependent on backup DNA repair pathways, which present an “Achilles heel” that can be targeted to eliminate cancer cells. This is the basis of synthetic lethality and is exemplified by the success of poly(ADP-ribose) polymerase (PARP) inhibitors in treating BRCA-deficient breast and ovarian cancers. However, new therapeutic strategies are urgently needed to overcome acquired and innate PARP inhibitor (PARPi) resistance and to exploit other DNA repair deficiencies. Optimism is increasing that targeting DNA polymerase θ (POLθ), which is involved in DNA repair, will not only synergize with PARPi's but may have broader utility in cancer treatment