Abstract 6098: Genome wide CRISPR screen reveals genetic vulnerabilities of next generation PARP1 inhibitor AZD5305
Bibliographic record
Abstract
Abstract The first-generation PARP inhibitors (PARPi) olaparib, niraparib, talazoparib and rucaparib have been clinically approved for several cancers, like breast, ovarian and prostate, especially in BRCA-mutant tumors which are of homologous recombination repair (HRR)-deficiency. All PARPi both target PARP1 and PARP2, causing cancer cell deaths deficient in HRR. However, only inhibition of PARP1 is required for synthetic lethality in HRR-deficient cells. AZD5305 is a highly selective PARP1 inhibitor which has been used in clinical trials. In this study, we used the Toronto Knock Out Library version 3 (TKOv3), which contains 70948 gRNAs targeting 18,053 protein-coding genes to perform whole-genome CRISPR-Cas9 screens with three isogenic cell lines 293A, MCF10A, and Hela to uncover known and new high-confidence genes synthetic lethal interacted with AZD5305. MAGeCK and Drug Z were used to analyze the results and genes were ranked according to their drugZ scores. We identify that in all three cell lines, PARP1 was in the top hit in positive selection which proves the AZD5305 indeed a PARP1 inhibitor. Moreover, through a comprehensive and comparative analysis with the screen results of first generation PARPi olaparib, we reveal known and new essential genes which are proved to be a common mechanism for synthetic lethality. We identify the gene AUNIP (Aurora Kinase A and Ninein Interacting Protein), in the top hit from AZD5305 screen but not in olaparib screen, suggesting that AUNIP may be an additional target for synthetic lethality with PARP1 loss. Taken together, this screen reveals the potential molecular genes related with PARP1 inhibitor that can be further explored targeted and combined cancer therapy. Citation Format: Ling Yin, Junjie Chen. Genome wide CRISPR screen reveals genetic vulnerabilities of next generation PARP1 inhibitor AZD5305 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6098.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".