HDAC/MIF dual inhibitor inhibits NSCLC cell survival and proliferation by blocking the AKT pathway

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Non-small-cell lung cancer (NSCLC) is a leading cause of cancer mortality.
• Current Tyrosine Kinase Inhibitor (TKI) therapies face challenges with resistance.
• Novel therapeutic strategies are urgently needed for NSCLC treatment.

Purpose of the Study:

• To develop and evaluate a novel small-molecule inhibitor targeting both Histone Deacetylase (HDAC) and Macrophage Migration Inhibitory Factor (MIF).
• To assess the efficacy of this dual inhibitor in TKI-resistant and EGFR-mutated NSCLC cell lines.
• To investigate the potential of the dual inhibitor to enhance TKI therapy.

Main Methods:

• Development of a small-molecule inhibitor targeting both HDAC and MIF.
• In vitro testing of the dual inhibitor on EGFR-mutated and EGFR-knockout NSCLC cell lines.
• Analysis of the effects of HDAC and MIF inhibition on cell survival and proliferation pathways (e.g., AKT).
• Combination studies with TKIs and the HDAC/MIF dual inhibitor.

Main Results:

• The HDAC/MIF dual inhibitor demonstrated toxicity against TKI-resistant and EGFR-mutated NSCLC cell lines.
• HDAC inhibition suppressed NSCLC cell survival and proliferation.
• MIF inhibition led to downregulation of pAKT/AKT, impacting cell survival.
• Combination therapy with TKIs and the dual inhibitor significantly enhanced TKI efficacy.

Conclusions:

• The novel HDAC/MIF dual inhibitor is a promising therapeutic candidate for NSCLC.
• Dual inhibition effectively targets key survival pathways in NSCLC cells.
• This approach offers a strategy to overcome TKI resistance and improve treatment outcomes in NSCLC.