SAHA triggered MET activation contributes to SAHA tolerance in solid cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• SAHA is FDA-approved for cutaneous T-cell lymphoma but shows limited success in solid tumors.
• Mechanisms of SAHA resistance in solid cancers are not fully understood.

Purpose of the Study:

• To investigate the mechanisms of SAHA resistance in solid cancer cell lines.
• To identify potential therapeutic strategies to overcome SAHA resistance.

Main Methods:

• Utilized prostate (PC3) and non-small cell lung (A549) cancer cell lines with limited SAHA sensitivity.
• Employed siRNA to silence MET and integrin α5β1.
• Assessed MET and AKT phosphorylation, apoptosis, and tumor growth inhibition.

Main Results:

• SAHA triggered MET and AKT phosphorylation in PC3 and A549 cells.
• MET silencing enhanced SAHA-induced apoptosis.
• Integrin α5β1 upregulation preceded MET activation and was crucial for it.
• Combination of SAHA and XL184 showed synergistic anti-cancer effects.

Conclusions:

• SAHA-induced MET activation is HGF-independent and mediated by integrin α5β1.
• This activation contributes to SAHA resistance in solid cancers.
• Combining SAHA with MET inhibitors warrants further clinical investigation for solid tumor treatment.