Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer

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Principal Investigator: Neil  Johnson
Organization: RESEARCH INST OF FOX CHASE CAN CTR
Fiscal Year: 2024
Award: $408,548
Funding agency: National Cancer Institute

PROJECT SUMMARY
Genetic disruption of DNA polymerase theta (Polθ) activity has been shown to effectively target BRCA1 mutated
cells, while leaving BRCA1 wild-type (WT) cells intact. Polθ facilitates theta-mediated DNA end joining (TMEJ)
repair by promoting DNA synapsis and repair synthesis at break sites containing 3' single stranded (ss)DNA
overhangs. Although small molecule inhibitors of Polθ activity are currently under development for the treatment
of BRCA1 mutant cancers, very little is known regarding the mechanisms that activate TMEJ and result in Polθ-
dependency in BRCA1 mutant cells. Moreover, the current paradigm assumes that homologous recombination
(HR)-deficiency confers Polθi sensitivity, therefore PARPi responsiveness is expected to be a biomarker for Polθ
inhibitor (Polθi) sensitivity. In our preliminary data, we unexpectedly identified commonly used Brca1 mutant
cells that grow relatively unperturbed with genetic Polq (Polθ) knockout (KO), indicating that Polθi and PARPi
sensitivity may not necessarily correlate. In this proposal, we will elucidate the molecular requirements for TMEJ
activation and identify biological factors that distinguish PARPi and Polθi sensitivity. We will address the following
Specific Aims: 1) reveal the molecular basis of TMEJ activation in Brca1 mutant cells; 2) uncover genetic Polθ-
dependencies in Brca1 mutant cells; and 3) examine pharmacologic Polθ inhibition in Brca1 mutant cells.
Collectively, these studies will be informative for future clinical studies employing Polθi.

Terms: <Abscission><Alleles><Allelomorphs><Assay><BRCA 1/2 mutations><BRCA mutations><BRCA1><BRCA1 Gene Product><BRCA1 Mutation><BRCA1 Protein><BRCA1 gene><BRCA1 gene mutation><BRCA1/2 mutations><BRCA1/2mut><BRCA2 Mutation><BRCA2 gene mutation><BRCAmut><Bioassay><Biologic Factor><Biological Assay><Biological Factors><Biological Markers><Breast><Breast Cancer><Breast Cancer 1 Gene><Breast Cancer 1 Gene Product><Breast Cancer Type 1 Susceptibility Gene><Breast Cancer Type 1 Susceptibility Protein><Breast-Ovarian Cancer Protein><Cancer Patient><Cancer Treatment><Cancer cell line><Cancers><Cell Body><Cell Line><CellLine><Cells><Cessation of life><Chromosomal Synapsis><Chromosome Pairing><Clinical><Clinical Research><Clinical Study><Collaborations><DNA><DNA Damage Repair><DNA Polymerases><DNA Repair><DNA Repair Pathway><DNA Replication><DNA Synthesis><DNA biosynthesis><DNA seq><DNA sequencing><DNA-Dependent DNA Polymerases><DNA-Directed DNA Polymerase><DNAseq><Data><Death><Deoxyribonucleic Acid><Dependence><Drug resistance><Early Onset Gene Breast Cancer 1><Early Onset Protein Breast Cancer 1><Event><Excision><Extirpation><Future><Genetic><Goals><Hereditary Breast Cancer 1><Human><Immunofluorescence Microscopy><In Vitro><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Malignant Breast Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Measures><Mediating><Modern Man><Molecular><Mutate><Names><Null Mouse><Outcome><Ovary Cancer><PARP Inhibitor><PARP Polymerase><PARP protein><PARP-1 inhibitor><PARPi><PARS><PDX model><Patient derived xenograft><Patients><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) Polymerases><Poly(ADP-ribose) polymerase 1 inhibitor><Poly(ADPribose) Polymerase><Polymerase><Process><Proteins><Publishing><RNF53><Removal><Reporter><Resistance><Role><Single-Stranded DNA><Site><Strains Cell Lines><Surgical Removal><Synapsis><Testing><United States><Unscheduled DNA Synthesis><Work><anti-cancer therapy><bio-markers><biologic marker><biomarker><brca 1 gene><cancer therapy><cancer-directed therapy><cell type><clinical applicability><clinical application><cultured cell line><develop therapy><drug resistant><homologous recombination><homologous recombination deficiency><homologous recombination repair deficiency><in vivo><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><insight><intervention development><malignancy><malignant breast tumor><mutant><name><named><naming><neoplasm/cancer><nuclease><ovarian cancer><patient derived xenograft model><patient population><patient stratification><pharmacologic><poly ADP polymerase><poly ADP ribose synthetase><pre-clinical development><preclinical development><refractory cancer><repair><repaired><resection><resistance to Drug><resistant><resistant cancer><resistant to Drug><small molecular inhibitor><small molecule><small molecule inhibitor><social role><ssDNA><stratified patient><therapeutic target><therapeutically effective><therapy development><treatment development><treatment strategy>