Adaptive responses to dasatinib-treated lung squamous cell cancer cells harboring DDR2 mutations

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• DDR2 mutations are found in 4% of lung squamous cell cancer (SCC).
• Dasatinib is a tyrosine kinase inhibitor investigated as a therapeutic option for lung SCC.
• Dasatinib's precise mechanism in DDR2-mutant SCC, including compensatory signaling, requires further elucidation.

Purpose of the Study:

• To investigate the global tyrosine phosphorylation (pY) changes induced by dasatinib in DDR2-mutant lung SCC cells.
• To identify adaptive resistance mechanisms and potential combination therapies for DDR2-mutant lung SCC.
• To assess the clinical relevance of observed signaling pathways in patient tissues.

Main Methods:

• Quantitative phosphoproteomics using mass spectrometry to analyze global tyrosine phosphorylation.
• Integration of phosphoproteomics data with protein-protein interaction networks.
• Small-molecule chemical library screening and synergistic drug combination studies.
• Analysis of receptor tyrosine kinase (RTK) phosphorylation in patient-derived lung SCC tissues.

Main Results:

• Dasatinib weakly inhibited ERK and AKT phosphorylation but decreased Src family kinase phosphorylation.
• Dasatinib exposure enhanced tyrosine phosphorylation of EGFR, MET, and IGF1R signaling complexes, indicating an adaptive RTK-driven response.
• Combination of dasatinib with MET and IGF1R inhibitors showed synergistic effects.
• EGFR and MET ligand stimulation rescued cells from dasatinib-induced viability loss.
• High levels of phosphorylated EGFR and MET were observed in DDR2-mutant lung SCC tissues.

Conclusions:

• DDR2-mutant lung SCC cells exhibit RTK-driven adaptive resistance mechanisms to dasatinib.
• Targeting MET and IGF1R in combination with dasatinib represents a promising therapeutic strategy.
• These findings support the rationale for cotargeting strategies in DDR2-mutant lung SCC.