Targeting the DNA Repair Enzyme Polymerase θ in Cancer Therapy

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 doublestrand 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. POLQ: Exploiting a Cancer Vulnerability for TherapyTo increase efficiency and lower the burden of toxic side effects, a major goal of cancer therapy is to progress from a 'one-drug-fits-all' to an individualized treatment approach tailored to the tumor-specific molecular features. Two main targeted therapeutic strategies are currently utilized in cancer treatment, both exploiting cancer-specific vulnerabilities. In the first approach, therapeutic suppression of aberrantly upregulated oncogenes alleviates the growth advantage of cancer cells. The second approach is based on the phenomenon that genetic alterations acquired by tumor cells cause their dependency on other compensatory pathways, loss of which leads to synthetic lethality (see Glossary). Therefore, therapeutic inhibition of pathways that are synthetic lethal with a cancer-specific alteration evokes cellular death in tumor cells while leaving normal cells unharmed [1]. The recent advent of genome-wide genetic interaction studies has demonstrated the extensive number of synthetic lethal interactions in cancer, many of which can potentially be translated to targeted cancer therapies [2].Cancer cells frequently acquire mutations in DNA repair genes and respond by rewiring their DNA repair network to utilize compensatory pathways for survival. Dependency on compensatory DNA repair pathways opens room for the development of cancer-specific small molecule inhibitors. A group of successful drugs that use this mode of action are poly(ADP-ribose) polymerase (PARP) inhibitors, approved for the treatment of BRCA-deficient cancers. The essentiality of PARP for cancer cells with loss-of-function mutations in BRCA1/2 is remarkable as such cancer cells are up to 1000 times more sensitive to PARP inhibitors than healthy cells [3,4]. Although challenges such as the acquisition of drug resistance need to be faced, the clinical success of inhibitory drugs targeting DNA repair enzymes is highly encouraging. In this context, the DNArepair enzyme polymerase θ (POLQ) has received increasing attention. POLQ is upregulated in numerous cancers and its overexpression is associated with poor prognosis [5][6][7][8][9]. Moreover, synthetic lethal interactions between POLQ and multiple DNA repair genes, including factors involv...

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

“…Another category of inhibitors targets proteins involved in DNA repair such as RAD51 and POLQ, respectively from the HR and MMEJ processes, or PARP and MTH1 [226][227][228][229]. The discovery of PARP inhibitors was a milestone for anticancer chemotherapies directed against DDR proteins.…”

Interfaces between cellular responses to DNA damage and cancer immunotherapy

“…Finally, the development and clinical exploration of inhibitors of DDR components such as ATR, ATM, and DNA-PK will shed more light on how these inhibitors potentially affect cellular immune responses and how these might be exploited in combinations with immune-targeting therapies. Furthermore, inhibitors targeting DNA repair polymerases, such as POLθ, represent an exciting arena for future studies, not only in the context of DDR alone but also in regards to their potential interplay with the cellular immune systems (Schrempf et al 2020). In this regard, it is of note that preclinical studies with POLθ inhibitors have indicated promising efficacies in tumor models, reminiscent of the initial studies when PARP inhibitors were being developed (Zhou et al 2020).…”

DNA polymerase theta suppresses mitotic crossing over

“…Moreover, a recent synthetic lethality screen uncovered 140 genes that have a synthetic growth defect with POLQ , most of which operate outside of DSB repair, and showed that as much as 30% of breast tumors may be relying on POLQ for survival [13]. This ability has motivated the search for a Pol θ inhibitor for treatment of cancer [36].…”