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Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
(NATURE RESEARCH, 2021-06-17)
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 ...
PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.
(AMER SOC CLINICAL INVESTIGATION INC, 2019-03-01)
The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA ...
Dissecting PARP inhibitor resistance with functional genomics.
(CURRENT BIOLOGY LTD, 2019-02-01)
The poly-(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib was the first licenced cancer drug that targeted an inherited form of cancer, namely ovarian cancers caused by germline BRCA1 or BRCA2 gene mutations. ...
Olaparib and temozolomide in desmoplastic small round cell tumors: a promising combination in vitro and in vivo.
(SPRINGER, 2020-07-01)
PURPOSE: Desmoplastic small round cell tumors (DSRCTs) are highly malignant and very rare soft tissue sarcomas with a high unmet need for new therapeutic options. Therefore, we examined poly(ADP-ribose) polymerase 1 (PARP1) ...
Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells.
(NATURE PUBLISHING GROUP, 2018-08-01)
BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome ...
Defining the true impact of coronavirus disease 2019 in the at-risk population of patients with cancer.
(ELSEVIER SCI LTD, 2020-09-01)
BACKGROUND: In light of the coronavirus disease 2019 (COVID-19) pandemic, cancer centres in the United Kingdom and Europe re-organised their services at an unprecedented pace, and many patients with cancer have had their ...
A decade of clinical development of PARP inhibitors in perspective.
(ELSEVIER, 2019-09-01)
Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce ...
Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.
(NATURE PORTFOLIO, 2020-05-29)
Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO ...
A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation.
(WILEY, 2018-12-01)
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2-related cancers. A test to identify additional HRR-deficient tumors ...
Modeling Therapy Resistance in BRCA1/2-Mutant Cancers.
(AMER ASSOC CANCER RESEARCH, 2017-09-01)
Although PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2 ...