Abstract B44: Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer
Bibliographic record
Abstract
Abstract Introduction: One of the major mechanisms of radioresistance in solid tumors is the activa-tion of the PI3K/Akt pathway in which Akt facilitates the repair of DNA double-strand breaks (DSBs) through stimulation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). As it is known that the PI3K/Akt pathway is hyperactivated in K-RAS mutated (K-RASmut), we investigated if targeting PI3K would be a potential approach for enhancing radiosensitivity of K-RASmut cells non-small lung cancer (NSCLC). Methods: The K-RASmut NSCLC cell lines A549 and H460 were utilized to examine the effect of PI3K inhibition on Akt signaling, non-homologous end joining (NHEJ) repair of DSBs, and post-irradiation cell survival. Results: Short-term (1-2 h) pre-treatment of K-RASmut cells with the PI3K inhibitor PI-103 (1 µM) inhibited Akt/DNA-PKcs activity, blocked DSBs repair and induced radiosensitivity, while long-term (24 h) pre-treatment did not. Lack of an effect in K-RASmut cells after 24 h of PI-103 pre-treatment was due to reactivation of K-Ras/MEK/ERK-dependent Akt. However, long-term treatment with PI-103 together MEK inhibitor PD98059 completely blocked reactivation of Akt and impaired DSBs repair through NHEJ leading to radiosensitization. The effect of PI3K inhibition on Akt signaling was also tested in A549 mouse xenografts in vivo. Akt and P-DNA-PKcs activity was inhibited 30 min post-irradiation in xenografts, which were pre-treated by PI-103 30 min before irradiation. However, after a 24 h pretreatment with PI-103, a significant reactivation of Akt was achieved 24 h after irradiation. Conclusion: Due to ERK-dependent reactivation of Akt in K-RAS mutated NSCLC cells, dual targeting of PI3K and MEK is an effective approach to induce radiosensitization. Acknowledgement: This work was supported by grants from the Deutsche Forschungsge-meinschaft (DFG, RO 527/7-1) awarded to HPR /MT and GRK 1302/2 (T11) awarded to MT/HPR. Citation Format: Mahmoud Toulany, Mari Ilda, Deric L. Wheeler, H. Peter Rodemann. Dual targeting of PI3K and MEK impairs DNA double-strand break repair as a relevant mechanism for radioresistance of K-RAS mutated non-small cell lung cancer [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 B44.
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".