Abstract A20: Synthetic lethality induced by pharmacological inhibition of ATM and PARP1
Bibliographic record
Abstract
Abstract DNA double-stranded breaks (DSBs) are highly deleterious and need to be repaired for maintaining genomic stability and viability. Cells resolve DSBs via non-homologous end-joining or homologous recombination repair (HRR). The simultaneous downregulation of both repair mechanisms induces synthetic lethality. Accordingly, PARP1 inhibitors (PARPi) are being used to target cancers with defective HRR such as cancers with BRCA1/2 mutations. Similar to BRCA1/2, ATM is involved in HRR; and ATM deficiency enhances sensitivity towards PARPi. But unlike BRCA1/2, ATM can be targeted using various small-molecule inhibitors (ATMi) in cancers containing wild type ATM. Using nasopharyngeal carcinoma cell lines as models, we found that the combined treatment of PARPi and ATMi led to the accumulation of DSBs, activation of the G2 DNA damage checkpoint, reduced mitotic entry, and diminished cell proliferation. Co-inhibition of ATM and PARP1 induced robust DNA damage responses without triggering mitotic catastrophe. In agreement with this, PARPi induced more DNA damage in ATM-knockout cells than wild type cells. Conversely, ATMi promoted more DNA damage when PARP1 was ablated. Although it is believed that PARPi exerts its effects by both inhibiting PARP1 catalytic activities and trapping PARP1 at DNA breaks, we found that the synergism between ATMi and PARPi did not require PARP1 trapping. These results provide insights on developing combined treatment of PARPi and ATMi into anti-cancer therapies for cancers without HRR or NHEJ deficiencies. Citation Format: Joyce Pui Ying Mak, Randy Yat Choi Poon. Synthetic lethality induced by pharmacological inhibition of ATM and PARP1 [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 A20.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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 teacher head, 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".