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Preprint WatchModerateSeptember 22nd, 2026

Autonomous MTOR activation in COPD airway epithelium impairs resolution through persistent mucus cell metaplasia and lysosome dysfunction

Kudrna, K., Vilches, F. L., Wang, X., Wang, J., Hugo, T., Bailey, K. L. et al.

Airway epithelial cells from COPD donors show IL-13-independent, autonomous MTOR activation (elevated RPS6, S6K1 and ULK1 phosphorylation) that suppresses lysosome function and sustains MUC5AC mucous cell metaplasia after cytokine withdrawal; MTOR inhibition partially rescues lysosome deficiency.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Kudrna and colleagues (bioRxiv, not peer reviewed) report that airway epithelial cells from COPD donors keep MTOR switched on without IL-13, with fewer functional lysosomes and MUC5AC metaplasia that fails to resolve, and that MTOR inhibition partly restores lysosome function in air-liquid interface cultures. The only MTOR failure in the Claidex graph is everolimus plus erlotinib in gemcitabine-refractory pancreatic cancer (everolimus-erlotinib-mtor-egfr-pancreatic-cancer-phase2-futility-termination), which stopped for toxicity and futility in an oncology setting with systemic dosing. The preprint does not contradict that failure. It points MTOR inhibition toward a different use, a local, epithelium-restricted intervention where the readout is lysosome recovery rather than tumor control. The evidence comes from donor cells and explant sections without in vivo dosing, so tolerability of chronic MTOR inhibition in COPD remains the open question the pancreatic record already flagged.

Abstract excerpt

Background: COPD is associated with persistent airway epithelial mucous cell metaplasia (MCM), mucin hypersecretion, and airway obstruction. Cytokines, such as IL-13, are well-known inflammatory drivers of airway MCM development. However, less is known about the factors that contribute to the impaired resolution of MCM in COPD. We hypothesized that MTOR activation in COPD airway epithelial cells (AECs) impairs autophagy and contributes to the delayed resolution of MCM. Methods: AEC from COPD and non-diseased donors were grown under air-liquid interface (ALI) conditions and treated with IL-13 to promote MCM. Airway sections from COPD lung explants or non-diseased lung donors were utilized for immunohistochemical and immunostaining. Lysosomes were assessed using molecular probes and immunostaining. Results: There was persistent MTOR-dependent MUC5AC immunostaining and epithelial hypertrophy in COPD AEC, which did not resolve after IL-13 withdrawal. MTOR substrate phosphorylation of RBS6, S6K1, and ULK1 was significantly elevated under baseline conditions, and at multiple timepoints independent of IL-13. Pharmacologic activation of MTOR led to increased IL-13-mediated MUC5AC levels in normal AEC but less robustly in COPD derived AEC. We hypothesized that persistent MTOR activation would reduce lysosome function and abundance in disease. COPD airways had reduced lysosome markers, LAMP1 and LAMP2 and fewer functional lysosomes by live-cell reporter probes. This lysosome deficiency in COPD AEC was partially rescued with MTOR inhibition. Conclusions: We provide evidence to support an axis of autonomous MTOR activation and impaired lysosome function in the COPD airway epithelium. Persistent MTOR signaling is a molecular driver that contributes to persistent MCM.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.