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Preprint WatchMildJune 2nd, 2026

AXL-GAS6/PROS1 Interaction: A Critical Switch Between Aberrant- and Healthy Repair Following Alveolar Lung Injury

Soetopo D, Mayr CH, Fundel-Clemens K, Ramirez F, Viollet C, Dick A, Rust W, Santacruz D, Hoevels Y, Applebee CJ, Legg S, Funk A, Schnapp G, Padget J, Strobel B, Thomas MJ, Ward SG, Larijani B, Geillinger-Kaestle K

Ligand-specific AXL signaling acts as a switch in alveolar repair, with GAS6 driving basal-cell proliferation and PROS1 opposing it, and AXL enriched in aberrant basaloid cells in IPF.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint sharpens AXL biology rather than contradicting the indexed failure. Claidex documents one AXL program, bemcentinib in advanced lung adenocarcinoma (bemcentinib-axl-lung-adenocarcinoma-phase1b2-supply-termination), which ended on a drug-supply and strategic decision rather than on efficacy or safety, so the target was never cleanly tested in that trial. The new work shows AXL signaling is ligand-dependent and context-specific in lung tissue, where GAS6 and PROS1 produce opposite effects on basal-cell proliferation and AXL concentrates in aberrant basaloid cells. That context dependence is a caution for any AXL inhibitor program. Blanket AXL blockade may hit a repair switch whose direction depends on local ligand balance, which complicates efficacy prediction and clean biomarker design. The signal is mild because the indexed failure was operational, not mechanistic, so the preprint adds nuance without overturning a documented efficacy result.

Abstract excerpt

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant alveolar repair and excessive fibrosis. The TAM-family receptor tyrosine kinase AXL, activated by GAS6 and PROS1, is implicated in tissue remodeling, but ligand-specific AXL signaling during alveolar repair remains poorly defined. Using single-cell RNA sequencing, primary human cell culture, functional spatial digital profiling, and in-vivo alveolar injury models, the authors show AXL is enriched in basal and aberrant basaloid cells of IPF patients. In vitro GAS6 increased basal-cell proliferation while PROS1 counteracted it, and spatial analysis demonstrated direct in-situ AXL-ligand interactions.

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.