Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
Diana ZatreanuHelen M R RobinsonOmar AlkhatibMarie BoursierHarry FinchLerin GeoDiego GrandeVera GrinkevichRobert A HealdSophie LangdonJayesh MajithiyaClaire L McWhirterNiall M B MartinShaun MooreJoana NevesEeson RajendraMarco RanzaniTheresia SchaedlerMartin StockleyKimberley WigginsRachel BroughSandhya SridharAditi GulatiNan ShaoLuned M BadderDaniela NovoEleanor G KnightRebecca MarlowSyed HaiderElsa CallenGraeme HewittJoost SchimmelRemko PrevoChristina AlliAmanda FerdinandCameron BellPeter BlencoweChris BotMathew CalderMark CharlesJayne CurryTennyson EkwuruKatherine EwingsWojciech KrajewskiEllen MacDonaldHollie McCarronLeon PangChris PedderLaurent RigoreauMartin E SwarbrickEd WheatleySimon WillisAi Ching WongAndre NussenzweigMarcel TijstermanAndrew TuttSimon J BoultonGeoff S HigginsStephen J PettittGraeme C M SmithChristopher J LordPublished in: Nature communications (2021)
To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.
Keyphrases
- dna repair
- dna damage
- small molecule
- induced apoptosis
- dna damage response
- circulating tumor
- hiv infected
- genome wide
- oxidative stress
- cell cycle arrest
- cell free
- antiretroviral therapy
- single molecule
- copy number
- breast cancer risk
- cell death
- papillary thyroid
- endoplasmic reticulum stress
- structural basis
- dna methylation
- gene expression
- working memory
- protein protein
- binding protein
- electronic health record
- transcription factor
- lymph node metastasis