Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors

Abstract

The most remarkable finding in synthetic lethality (SL) is the hypersensitivity to PARP inhibitors (PARPis) of the tumors harboring defects in genes involved in homologous repair (HR) such as BRCA1/2. Despite initial responsiveness to PARPi, the penetrance of the synthetic lethal interactions between BRCA1/2 genes and PARPi is incomplete. Thus, a significant proportion of HR-defective tumors experience intrinsic or acquired resistance, representing a key challenge of clinical research. An expanded concept of SL is opening new ways and includes novel forms of genetic interactions, investigating not only traditional SL of pairs genes but also SL between biological pathways that regulate the same essential survival cell function. In this context, recent research showed that HR and theta-mediated end-joining (TMEJ) pathways exhibit SL. DNA polymerase theta (Polθ) is encoded by the POLQ gene and is a key component of the TMEJ, an essential backup pathway, intrinsically mutagenic, to repair resected double-strand breaks (DSBs) when the non-homologous end joining (NHEJ) and HR are impaired. Polθ is broadly expressed in normal tissues, overexpressed in several cancers, and typically associated with poor outcomes and shorter relapse-free survival. Notably, HR-deficient tumor cells present the characteristic mutational signatures of the error-prone TMEJ pathway. According to this observation, the loss of HR proteins, such as BRCA1 or BRCA2, contributes to increasing the TMEJ-specific genomic profile, suggesting synthetic lethal interactions between loss of the POLQ and HR genes, and resulting in the emerging interest for Polθ as a potential therapeutic target in BRCA1/2-associated tumors.This review summarizes the converging roles of the POLQ and HR genes in DNA DSB repair, the early-stage clinical trials using Polθ inhibitor to treat HR-defective tumors and to overcome BRCA-reversion mutations responsible for therapeutic resistance, and the novel pleiotropic effects of Polθ, paving the way for the development of unexplored synthetic lethality strategies.

Fig. 1. PARP inhibition and synthetic lethality in BRCA-deficient cells.

a In the BRCA-proficient cells the HR repair system is physiologically involved in DNA repair, with DNA damage correctly repaired; b In the BRCA-deficient cells, the absence of efficient homologous recombination, along with the PARP-inhibition, leads to the use of base excision repair (BER) as compensatory pathway, resulting in genomic instability and cell death.

Fig. 2. Pleiotropic Polθ influence of different repair mechanism systems and molecular pathways.

Beyond BRCA-mutated tumors, Polθ showed synthetic lethal interactions also with other DNA repair-related genes that control DSB repair and HR, such as 53BP1, RAD52, PALB2, and FANCD2. Furthermore, the effect of the cGAS-STING immunological and inflammatory pathway, on the MMEJ repair system through APE2, and the synergy with radiotherapy, was recently highlighted (Created with BioRender.com).

Fig. 3. Polθ structure and Polθ-chemical inhibitors.

a 3D structure of the Polθ-helicase and polymerase domains (PDB code 5AGA; PDB code 6XBU); b 2D-Chemical structures of Polθ-hel inhibitors: size-expanded nucleotides [1]; heteroarylmethylene and acetamido derivatives [2]; ART558, ART812 and RP-6685 [3]; thiazoleurea and heterocyclic substituted urea derivatives [4]. 2D-Chemical structures of Polθ-pol inhibitors: thiadiazole derivatives and novobiocin [5].