An organoid library unveils subtype-specific IGF-1 dependency via a YAP-AP1 axis in human small cell lung cancer.

Summary

A 40-line patient-derived SCLC organoid library demonstrates that non-neuroendocrine SCLC depends on IGF-1–driven activation of YAP1 and AP1, rendering this axis therapeutically targetable, while NE-type organoids are niche-factor independent. TP53/RB1 double loss reprograms alveolar cells toward airway-like fate and IGF-1 dependency.

Key Findings

• Non-NE SCLC organoids require IGF-1–driven activation of YAP1 and AP1 for growth; NE-type organoids are niche-factor independent.
• Pharmacologic targeting of IGF-1, YAP1, or AP1 suppresses non-NE SCLC organoid growth.
• TP53/RB1 co-loss in human alveolar cells induces airway-like lineage and IGF-1 dependency, linking genotype to phenotype.

Clinical Implications

Supports biomarker-driven stratification of SCLC to prioritize IGF-1/YAP/AP1 pathway inhibition in non-NE subtypes; motivates clinical trials testing IGF-1 axis or YAP/AP1 inhibitors with rational patient selection.

Limitations

• Preclinical organoid models may not fully recapitulate tumor–microenvironment interactions in vivo.
• Clinical efficacy and safety of targeting IGF-1/YAP/AP1 in SCLC remain to be established.

Future Directions

Prospective trials with subtype stratification to evaluate IGF-1/YAP/AP1 inhibition; refine biomarkers (YAP1/POU2F3 expression, IGF-1 signaling readouts) for patient selection.