PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors

PMCID: PMC12177050

PMID: 40533463

DOI: 10.1038/s41419-025-07767-x

Journal: Cell death & disease

Publication Date: 2025-6-18

Authors: Zhang X, Xu J, Wang X, Xu L, Zhang X, et al.

Key Points

• CYH33 demonstrates potent anti-proliferative activity against HNSCC, including cisplatin-resistant cell lines
• Achieved significant tumor growth inhibition in xenograft models (20 mg/kg dosage)
• Suggests combination therapy with EGFR inhibition as a promising approach for HNSCC treatment

Summary

This study investigated CYH33, a novel PI3Kα-selective inhibitor, as a potential therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). The researchers comprehensively evaluated CYH33's anti-tumor mechanisms, demonstrating promising activity against HNSCC cell lines, including cisplatin-resistant variants. Using advanced phosphoproteomics, they uncovered that CYH33's efficacy extends beyond PI3K/Akt pathway inhibition, with particular emphasis on attenuating Erk phosphorylation and GAB1 membrane localization.

The research revealed that CYH33 exhibited superior anti-proliferative activity compared to existing PI3Kα inhibitors like alpelisib, with IC50 values below 2 μM in most HNSCC cell lines. In vivo xenograft studies confirmed its therapeutic potential, showing significant tumor growth inhibition without substantial weight loss. Notably, the study suggested that concurrent EGFR inhibition could synergistically enhance CYH33's anti-tumor activity, providing a rational combination strategy for HNSCC treatment.