9 research outputs found
Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma
High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations
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MECHANISM OP ACTION OP p-HYDROXYBENZOATE HYBROZYLASE FROMPseudomonas putida. III. THE ENZYME-SUBTRATE COMPLEX
The mechanism of action of p-hydroxybenzoate hydroxylase from Pseudomonas putida, strain M-6, has been investigated. The aromatic substrate analogues, benzoate, p-fluorobenzoate, p-chlorobenzoate, p-nitrobenzoate, p-aminobenzoate, and 6-hydroxynicotinate, are found to be competitive inhibitors. This finding differs from the previously reported noncompetitive behavior in a different buffer system. The optical activity of the enzyme-inhibitor complex is studied. From the kinetic and circular dichroism (CD) measurements, they have found that the carboxyl moiety is necessary and sufficient for the enzyme-substrate binding, whereas the hydroxyl group alone will not lead to binding. There are two classes of inhibitory analogues: one causes changes in CD spectra of the enzyme similar to those evoked by the substrate, and the other does not cause significant changes. the results indicate that more than one mode of enzyme-inhibitor interaction is involved. The CD of the enzyme-NADPH complex under anaerobic conditions suggests that the oxidized enzyme and reduced pyridine nucleotide form a complex, both in the absence and presence of the substrate, p-hydroxybenzoate. Furthermore, evidence for a ternary complex is given
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