Role of the mTOR Pathway and Autophagy in Mediating PARP Inhibitor Sensitivity in Small Cell Lung Cancer
Bibliographic record
Abstract
Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a dismal 5-year survival rate of 7%. Despite initial response rates (70-80%) to DNA damaging agents, patient relapse accompanied with treatment resistance is inevitable. Poly (ADP)-ribose inhibitors (PARPi) are a novel therapy that has been evaluated for SCLC treatment and are in clinical trials. There is increasing interest in identifying targetable factors involved in PARPi sensitization for combinatorial therapeutic strategies. This study shows that the mTOR pathway mediates PARPi sensitivity in SCLC cells through CRISPR genetic screens. We hypothesized that the constitutive activation of mTORC1 suppresses pro-survival autophagy. We used functional genetic validation with shRNAs to knock down the TSC1/2 complex and observed significant sensitization of SCLC cells to PARPi. Our data support that pharmacologically inhibiting autophagy is synergistic with PARPi in SCLC cells, creating a novel avenue for developing combination therapies to improve overall survival for SCLC patients.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".