scholarly journals Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Stephen J. Pettitt ◽  
Dragomir B. Krastev ◽  
Inger Brandsma ◽  
Amy Dréan ◽  
Feifei Song ◽  
...  
Keyword(s):  
Parp Inhibitor ◽  
Point Mutations ◽  
High Density ◽  
Genome Wide ◽  
Inhibitor Resistance

scholarly journals Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

2017 ◽  
Author(s):  
Stephen J. Pettitt ◽  
Dragomir B. Krastev ◽  
Inger Brandsma ◽  
Amy Drean ◽  
Feifei Song ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Point Mutations ◽  
Underlying Mechanism ◽  
Parp Inhibitors ◽  
High Density ◽  
Single Amino Acid ◽  
Genome Wide ◽  
Amino Acid Mutations

AbstractPARP inhibitors (PARPi) target homologous recombination defective tumour cells via synthetic lethality. Genome-wide and high-density CRISPR-Cas9 “tag, mutate and enrich” mutagenesis screens identified single amino acid mutations in PARP1 that cause profound PARPi-resistance. These included PARP1 mutations outside of the DNA interacting regions of the protein, such as mutations in solvent exposed regions of the catalytic domain and clusters of mutations around points of contact between ZnF, WGR and HD domains. These mutations altered PARP1 trapping, as did a mutation found in a clinical case of PARPi resistance. These genetic studies reinforce the importance of trapped PARP1 as a key cytotoxic DNA lesion and suggest that interactions between non-DNA binding domains of PARP1 influence cytotoxicity. Finally, different mechanisms of PARPi resistance (BRCA1 reversion, PARP1, 53BP1, REV7 mutation) had differing effects on chemotherapy sensitivity, suggesting that the underlying mechanism of PARPi resistance likely influences the success of subsequent therapies.

scholarly journals The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment

2020 ◽  
Vol 6 (51) ◽  
pp. eabb8626
Author(s):  
Szilvia Juhász ◽  
Rebecca Smith ◽  
Tamás Schauer ◽  
Dóra Spekhardt ◽  
Hasan Mamar ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Dna Lesions ◽  
End Joining ◽  
Multiple Tumor ◽  
Genome Wide ◽  
A Genome ◽  
Inhibitor Resistance ◽  
Tumor Types

Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of BRCA-deficient cancers, with treatments currently extending toward other homologous recombination defective tumors. In a genome-wide CRISPR knockout screen with olaparib, we identify ALC1 (Amplified in Liver Cancer 1)—a cancer-relevant poly(ADP-ribose)-regulated chromatin remodeling enzyme—as a key modulator of sensitivity to PARP inhibitor. We found that ALC1 can remove inactive PARP1 indirectly through binding to PARylated chromatin. Consequently, ALC1 deficiency enhances trapping of inhibited PARP1, which then impairs the binding of both nonhomologous end-joining and homologous recombination repair factors to DNA lesions. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Together, we conclude that ALC1-dependent PARP1 mobilization is a key step underlying PARP inhibitor resistance.

Abstract 410: Genome-wide and focused CRISPR screens to study PARP inhibitor resistance mediated by mutations inPARP1

2018 ◽  
Author(s):  
Stephen J. Pettitt ◽  
Dragomir B. Krastev ◽  
Inger Brandsma ◽  
Amy Dréan ◽  
Feifei Song ◽  
...  
Keyword(s):  
Parp Inhibitor ◽  
Genome Wide ◽  
Inhibitor Resistance

P6017 A high density genome-wide scan for genetic risk factors of insect bite hypersensitivity (IBH): A Horsegene Project Initiative

2016 ◽  
Vol 94 (suppl_4) ◽  
pp. 156-157
Author(s):  
B. D. Velie ◽  
M. Shrestha ◽  
L. Francois ◽  
A. Schurink ◽  
A. Stinckens ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
High Density ◽  
Genome Wide ◽  
Insect Bite Hypersensitivity ◽  
Genome Wide Scan

scholarly journals Genome-Wide High-Density SNP Linkage Search for Glioma Susceptibility Loci: Results from the Gliogene Consortium

2011 ◽  
Vol 71 (24) ◽  
pp. 7568-7575 ◽  
Author(s):  
Sanjay Shete ◽  
Ching C. Lau ◽  
Richard S. Houlston ◽  
Elizabeth B. Claus ◽  
Jill Barnholtz-Sloan ◽  
...  
Keyword(s):  
High Density ◽  
Susceptibility Loci ◽  
Genome Wide

scholarly journals Novel genes identified in a high-density genome wide association study for nicotine dependence

2006 ◽  
Vol 16 (1) ◽  
pp. 24-35 ◽  
Author(s):  
Laura Jean Bierut ◽  
Pamela A.F. Madden ◽  
Naomi Breslau ◽  
Eric O. Johnson ◽  
Dorothy Hatsukami ◽  
...  
Keyword(s):  
Association Study ◽  
Nicotine Dependence ◽  
Genome Wide Association Study ◽  
High Density ◽  
Genome Wide Association ◽  
Novel Genes ◽  
Genome Wide

Abstract 2052: TRIP13 amplification confers PARP inhibitor resistance and polymerase theta inhibitor sensitivity

2021 ◽  
Author(s):  
Jeffrey Patterson-Fortin ◽  
Jia Zhou ◽  
Alan D'Andrea
Keyword(s):  
Parp Inhibitor ◽  
Inhibitor Resistance

Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian cancer (HGOC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5537-5537
Author(s):  
Tanya Kwan ◽  
Amit M. Oza ◽  
Domenica Lorusso ◽  
Carol Aghajanian ◽  
Ana Oaknin ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Maintenance Treatment ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Molecular Characteristics ◽  
Brca Mutations ◽  
Molecular Features ◽  
Brca1 Promoter Methylation ◽  
Genome Wide ◽  
To Receive

5537 Background: ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor (PARPi) rucaparib as maintenance treatment in HGOC patients (pts) who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. Methods: Pts were randomized 2:1 to receive rucaparib 600 mg BID or placebo. At the data cutoff of Dec 31, 2019, 33/375 (9%) and 1/189 (0.5%) pts were still ongoing and receiving rucaparib or placebo, respectively. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were compared between pts who derived exceptional benefit (PFS ≥2 yrs), and those with disease progression on first scan (≈12 wks; the short-term [ST] subgroup) within each treatment arm. Results: Of 564 pts, 83 (15%) showed exceptional benefit: 79/375 (21%) in the rucaparib arm and 4/189 (2%) in the placebo arm. Within the rucaparib arm, exceptional benefit pts had more favorable clinical prognostic factors at baseline compared with the ST subgroup (Table). While BRCA mutations were enriched in the rucaparib exceptional benefit subgroup, 34/79 (43%) of these pts were BRCA wild type. Among other biomarkers, RAD51C/D mutations were associated with exceptional benefit; low genome-wide loss of heterozygosity was enriched within the ST subgroup; and high BRCA1 methylation was present at similar fractions. Trends were similar in the placebo arm (Table). Conclusions: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, pts with favorable clinical characteristics and known mechanisms of PARPi sensitivity. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of HGOC pts. Clinical trial information: NCT01968213. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document