Abstract PR04: Mechanism for PARPi resistance: Homologous recombination without BRCA1
Bibliographic record
Abstract
Abstract Approximately 15-20% of all epithelial ovarian cancers harbor germline or somatic mutations in BRCA1/2. Despite PARP inhibitor induce synthetic lethality in non-cancerous mouse embryo fibroblast cells that harbor BRCA1/2 mutations, a substantial fraction of BRCA1/2-mutated tumors patients do not respond to PARPi treatment, and a large fraction of BRCA1/2-mutated tumors patients eventually develop resistance to PARPi suggest significant frequency of acquired mutation lead to PARPi resistance preventing complete cure. We use CRISPR based library screen identified ATMIN/DYNLL1 loss as strong candidate for PARPi and cisplatin resistance mechanism. Targeted mutation on ATMIN or its transcription target DYNLL1 lead to increase of Cisplatin IC50 up to 200% and Olaparib IC50 up to 400%. More interestingly, ATMIN/DYNLL1 loss lead to restoration of Homologous recombination in BRCA1 mutant cells. ATMIN is under-expressed in about 30% ovarian cancer patient and low ATMIN expression correlate with shorter survival. Since ATMIN is important for DNA base damage repair but not Double Strand Break repair, we hypothesis ATMIN play important role in DNA damage repair pathway choice to suppress DSB repair while promote DNA base damage repair. Cells with mutant BRCA1 and loss ATMIN/DYNLL1 may result in abnormal DSB repair activity and lead to resistance to DNA damage agent such as Olaparib and Cisplatin. This abstract is also being presented as Poster A18. Citation Format: Yizhou Joseph He, Khyati Meghani, Dipanjan Chowdhury. Mechanism for PARPi resistance: Homologous recombination without BRCA1 [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR04.
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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 | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.011 | 0.004 |
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".