The hedgehog processing pathway is required for NSCLC growth and survival

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Hedgehog (HH) signaling is crucial for various cancers, including non-small cell lung carcinoma (NSCLC).
• Smoothened (SMO) antagonists are clinically used but face resistance due to SMO mutations.
• Therapeutic strategies targeting HH signaling upstream of SMO are needed.

Purpose of the Study:

• To investigate the efficacy of targeting HH ligand processing for inhibiting HH-dependent NSCLC growth.
• To identify potential therapeutic targets in the HH pathway upstream of SMO.
• To evaluate the clinical relevance of HH processing in NSCLC.

Main Methods:

• Utilized lentivirally delivered shRNA to knockdown HH-processing proteins (SKN and DISP-1) in NSCLC cell lines.
• Assessed the impact of gene knockdown on cell proliferation and cell death.
• Evaluated tumor growth in mouse xenograft models.
• Analyzed SKN and DISP-1 expression in primary NSCLC clinical specimens.

Main Results:

• Knockdown of SKN or DISP-1 significantly reduced NSCLC cell proliferation and increased cell death.
• Exogenous HH ligand or SMO agonist reversed the anti-proliferative effects.
• Inhibition of HH processing abrogated tumor growth in mouse xenografts.
• SKN was frequently overexpressed, and higher DISP-1 expression correlated with unfavorable outcomes in NSCLC patients.

Conclusions:

• HH ligand processing is critical for HH-dependent tumor growth.
• SKN and DISP-1 represent potential druggable targets in the HH pathway.
• Targeting HH processing offers a promising therapeutic strategy for HH ligand-dependent cancers, including NSCLC.