@article {1656925,
	title = {Targeting DNA Repair with Combined Inhibition of NHEJ and MMEJ Induces Synthetic Lethality in TP53-Mutant Cancers},
	journal = {Cancer Res},
	volume = {82},
	number = {20},
	year = {2022},
	month = {2022 Oct 17},
	pages = {3815-3829},
	abstract = {UNLABELLED: 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.

SIGNIFICANCE: Combined inhibition of NHEJ and MMEJ using two nontoxic, targeted DNA repair inhibitors can effectively induce toxic DNA damage to treat TP53-deficient cancers.},
	keywords = {DNA, DNA End-Joining Repair, DNA Repair, DNA-Activated Protein Kinase, DNA-Directed DNA Polymerase, Humans, Neoplasms, Novobiocin, Pyridazines, Quinazolines, Synthetic Lethal Mutations, Tumor Suppressor Protein p53},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-22-1124},
	author = {Patterson-Fortin, Jeffrey and Bose, Arindam and Tsai, Wei-Chih and Grochala, Carter and Nguyen, Huy and Zhou, Jia and Parmar, Kalindi and Lazaro, Jean-Bernard and Liu, Joyce and McQueen, Kelsey and Shapiro, Geoffrey I and Kozono, David and D{\textquoteright}Andrea, Alan D}
}
