Targeting DNA Repair with Combined Inhibition of NHEJ and MMEJ Induces Synthetic Lethality in TP53-Mutant Cancers

by Selleckchem | Aug 12 2023

DNA repair pathway inhibitors are a new class of anticancer drugs that are advancing in clinical trials. Peposertib is an inhibitor of DNA-dependent protein kinase (DNA-PK), which is a key driver of nonhomologous end-joining (NHEJ). To identify regulators of response to peposertib, we performed a genome-wide CRISPR knockout screen and found that loss of POLQ (polymerase theta, POLθ) and other genes in the microhomology-mediated end-joining (MMEJ) pathway are key predictors of sensitivity to DNA-PK inhibition. Simultaneous disruption of two DNA repair pathways via combined treatment with peposertib plus a POLθ inhibitor novobiocin exhibited synergistic synthetic lethality resulting from accumulation of toxic levels of DNA double-strand break end resection. TP53-mutant tumor cells were resistant to peposertib but maintained elevated expression of POLQ and increased sensitivity to novobiocin. Consequently, the combination of peposertib plus novobiocin resulted in synthetic lethality in TP53-deficient tumor cell lines, organoid cultures, and patient-derived xenograft models. Thus, the combination of a targeted DNA-PK/NHEJ inhibitor with a targeted POLθ/MMEJ inhibitor may provide a rational treatment strategy for TP53-mutant solid tumors.

Comments:

The passage you provided describes a study on DNA repair pathway inhibitors as potential anticancer drugs. Specifically, the researchers focused on peposertib, an inhibitor of DNA-dependent protein kinase (DNA-PK), which plays a role in nonhomologous end-joining (NHEJ), a DNA repair mechanism.

The study employed a genome-wide CRISPR knockout screen to identify genes that regulate the response to peposertib. The results indicated that loss of POLQ (polymerase theta, POLθ) and other genes involved in microhomology-mediated end-joining (MMEJ) pathway predict sensitivity to DNA-PK inhibition. In simpler terms, disrupting the MMEJ pathway in combination with DNA-PK inhibition could enhance the effectiveness of the treatment.

To investigate this further, the researchers conducted experiments using a POLθ inhibitor called novobiocin in combination with peposertib. They discovered that simultaneously targeting both the NHEJ pathway (through DNA-PK inhibition) and the MMEJ pathway (through POLθ inhibition) resulted in a synergistic effect, leading to synthetic lethality. Synthetic lethality refers to a situation where the simultaneous disruption of two specific pathways or genes is more lethal to cancer cells than targeting either pathway or gene alone.

Moreover, the study found that tumor cells with TP53 mutations (TP53-mutant) were resistant to peposertib but exhibited elevated expression of POLQ. This increased expression of POLQ made the TP53-mutant cells more sensitive to novobiocin. Consequently, the combination of peposertib and novobiocin resulted in synthetic lethality specifically in TP53-deficient tumor cell lines, organoid cultures, and patient-derived xenograft models.

In summary, the researchers propose that the combination of a targeted DNA-PK/NHEJ inhibitor (peposertib) with a targeted POLθ/MMEJ inhibitor (novobiocin) could be a promising treatment strategy for TP53-mutant solid tumors. This approach aims to exploit the synthetic lethality resulting from the simultaneous disruption of two DNA repair pathways, leading to the accumulation of toxic levels of DNA double-strand break end resection and ultimately inducing cell death in TP53-deficient cancer cells.