Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

Zatreanu, Diana; Robinson, Helen M.R.; Alkhatib, Omar; Boursier, Marie; Finch, Harry; Geo, Lerin; Grande, Diego; Grinkevich, Vera; Heald, Robert A.; Langdon, Sophie; Majithiya, Jayesh B.; McWhirter, Claire; Martin, Niall M.B.; Moore, Susan; Neves, Joana; Rajendra, Eeson; Ranzani, Marco; Schaedler, Theresia; Stockley, Martin L.; Wiggins, Kimberley; Brough, Rachel; Sridhar, Sandhya; Gulati, Aditi; Shao, Nan; Badder, Luned; Novo, Daniela; Knight, Eleanor; Marlow, Rebecca; Haider, Syed; Callén, Elsa; Hewitt, Graeme; Schimmel, Joost; Prevo, Remko; Alli, Christina; Ferdinand, Amanda; Bell, Cameron; Blencowe, Peter; Bot, Christopher; Calder, Mathew; Charles, Mark; Curry, Jane; Ekwuru, Tennyson; Ewings, Katherine; Krajewski, Wojciech; MacDonald, Ellen; McCarron, Hollie; Pang, Leon; Pedder, Chris; Rigoreau, Laurent; Swarbrick, Martin E.; Wheatley, Ed; Willis, Simon N.; Wong, Ai Ching; Nussenzweig, André; Tijsterman, Marcel; Tutt, Andrew; Boulton, Simon J.; Higgins, Geoff S.; Pettitt, Stephen J.; Smith, Graeme C.M.; Lord, Christopher J.

doi:10.1038/s41467-021-23463-8

Cited by 221 publications

(272 citation statements)

References 66 publications

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“…Lastly, POLQ gene suppression appears to be additive or synergistic with PARPi and DNA damaging agents in killing HR defective cells [14]. Consistent with this, a recently reported potent and selective Polθ polymerase (Polθ-pol) inhibitor developed by Artios Pharma acts additively with PARPi in HR-deficient cells and selectively kills HR-deficient cells as a single agent at low micromolar concentrations [54]. Because Polθ confers resistance to IR and topoisomerase inhibitors (i.e., etoposide, camptothecin) [20,22], Polθ inhibitors are also expected to reduce cellular resistance to these widely used cancer therapies that also cause DNA breaks and replicative stress.…”

Section: Polθ Enzymatic Domains As Drug Targetsmentioning

confidence: 63%

“…Taken together, multiple lines of evidence demonstrate that both Polθ enzymatic domains contribute to MMEJ and the survival of HR-deficient cells. Consistent with this small-molecule inhibition of either domain causes the preferential killing of BRCA-deficient cells [54,57]. For example, in addition to the synthetic lethal effects observed for Artios Pharma's Polθ-pol inhibitor, a recent paper indicates that small-molecule inhibition of Polθ-hel also induces synthetic lethality in BRCA-deficient cells [57].…”

Section: Polθ Enzymatic Domains As Drug Targetsmentioning

confidence: 78%

“…In support of this, all of the reported synthetic lethal studies on Polθ used either CRISPR/Cas9 or shRNA to respectively knockout or strongly suppress the expression of Polθ, which is equivalent to simultaneous inactivation of both enzymatic domains (https://depmap.org/portal/ccle/ accessed on 1 May 2021) [ Taken together, multiple lines of evidence demonstrate that both Polθ enzymatic domains contribute to MMEJ and the survival of HR-deficient cells. Consistent with this, small-molecule inhibition of either domain causes the preferential killing of BRCA-deficient cells [54,57]. For example, in addition to the synthetic lethal effects observed for Artios Pharma's Polθ-pol inhibitor, a recent paper indicates that small-molecule inhibition of Polθ-hel also induces synthetic lethality in BRCA-deficient cells [57].…”

Section: Polθ Enzymatic Domains As Drug Targetsmentioning

confidence: 79%

“…Because Polθ confers resistance to IR and topoisomerase inhibitors (i.e., etoposide, camptothecin) [20,22], Polθ inhibitors are also expected to reduce cellular resistance to these widely used cancer therapies that also cause DNA breaks and replicative stress. Indeed, Artios Pharma's Polθ-pol inhibitor significantly reduced cellular resistance to IR [54]. Polθ inhibitors are also likely to act synergistically with platinum-based chemotherapy agents in HR-deficient cells based on genetic studies [23].…”

Section: Polθ Enzymatic Domains As Drug Targetsmentioning

confidence: 99%

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DNA Polymerase θ: A Cancer Drug Target with Reverse Transcriptase Activity

Chen

Pomerantz

2021

Genes

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The emergence of precision medicine from the development of Poly (ADP-ribose) polymerase (PARP) inhibitors that preferentially kill cells defective in homologous recombination has sparked wide interest in identifying and characterizing additional DNA repair enzymes that are synthetic lethal with HR factors. DNA polymerase theta (Polθ) is a validated anti-cancer drug target that is synthetic lethal with HR factors and other DNA repair proteins and confers cellular resistance to various genotoxic cancer therapies. Since its initial characterization as a helicase-polymerase fusion protein in 2003, many exciting and unexpected activities of Polθ in microhomology-mediated end-joining (MMEJ) and translesion synthesis (TLS) have been discovered. Here, we provide a short review of Polθ‘s DNA repair activities and its potential as a drug target and highlight a recent report that reveals Polθ as a naturally occurring reverse transcriptase (RT) in mammalian cells.

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Section: Polθ Enzymatic Domains As Drug Targetsmentioning

confidence: 63%

Section: Polθ Enzymatic Domains As Drug Targetsmentioning

confidence: 78%

Section: Polθ Enzymatic Domains As Drug Targetsmentioning

confidence: 79%

Section: Polθ Enzymatic Domains As Drug Targetsmentioning

confidence: 99%

See 2 more Smart Citations

DNA Polymerase θ: A Cancer Drug Target with Reverse Transcriptase Activity

Chen

Pomerantz

2021

Genes

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“…Artios Pharma (Cambridge, UK) will be initiating IND on their first-in-class compounds (https://www.artiospharma.com/science/#pipeline, accessed 23 August 2021), likely targeting the template-dependent DNA polymerase activity of pol θ [72]. A contribution from Zatreanu and colleagues reports on a series of compounds demonstrating high potency against DNA synthesis by pol θ in vitro [27]. These inhibitors do not compete with nucleotides at the pol-active site.…”

Section: First-in-class Inhibitors Of Pol θ Enzymatic Functionsmentioning

confidence: 99%

Polymerase θ Coordinates Multiple Intrinsic Enzymatic Activities during DNA Repair

Zahn

Jensen

2021

Genes

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The POLQ gene encodes DNA polymerase θ, a 2590 amino acid protein product harboring DNA-dependent ATPase, template-dependent DNA polymerase, dNTP-dependent endonuclease, and 5′–dRP lyase functions. Polymerase θ participates at an essential step of a DNA double-strand break repair pathway able to join 5′-resected substrates by locating and pairing microhomologies present in 3′-overhanging single-stranded tails, cleaving the extraneous 3′-DNA by dNTP-dependent end-processing, before extending the nascent 3′ end from the microhomology annealing site. Metazoans require polymerase θ for full resistance to DNA double-strand break inducing agents but can survive knockout of the POLQ gene. Cancer cells with compromised homologous recombination, or other DNA repair defects, over-utilize end-joining by polymerase θ and often over-express the POLQ gene. This dependency points to polymerase θ as an ideal drug target candidate and multiple drug-development programs are now preparing to enter clinical trials with small-molecule inhibitors. Specific inhibitors of polymerase θ would not only be predicted to treat BRCA-mutant cancers, but could thwart accumulated resistance to current standard-of-care cancer therapies and overcome PARP-inhibitor resistance in patients. This article will discuss synthetic lethal strategies targeting polymerase θ in DNA damage-response-deficient cancers and summarize data, describing molecular structures and enzymatic functions.

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Resistance to DNA repair inhibitors in cancer

et al. 2022

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The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre-clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polh (Pol-Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.Abbreviations ATR, Ataxia telangiectasia and Rad3 related gene; BRCA1, BRCA1 DNA repair-associated gene; BRCA2, BRCA2 DNA repair-associated gene; ctDNA, circulating tumour DNA; DDR, DNA damage response network; HR, homologous recombination; MMR, mismatch DNA repair; NAD+, nicotinamide adenine dinucleotide; PAR, poly-ADP-ribose; PARP1, poly-(ADP-ribose) polymerase 1 gene; PARPi, PARP inhibitor; POLQ, DNA polymerase theta gene, protein known as Polh; RS, replication stress; SWI/SNF, SWItch/sucrose non-fermentable chromatin remodelling complex; TMEJ, theta-mediated end joining; VEGF, vascular endothelial growth factor; WGR, protein domain containing tryptophan (W), glycine (G), arginine (R); WRN, Werner syndrome ATP-dependent helicase gene; ZnF, Zinc Finger protein domain.

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Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

Cited by 221 publications

References 66 publications

DNA Polymerase θ: A Cancer Drug Target with Reverse Transcriptase Activity

DNA Polymerase θ: A Cancer Drug Target with Reverse Transcriptase Activity

Polymerase θ Coordinates Multiple Intrinsic Enzymatic Activities during DNA Repair

Resistance to DNA repair inhibitors in cancer

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