Lefamulin Overcomes Acquired Drug Resistance via Regulating Mitochondrial Homeostasis by Targeting ILF3 in...

Area of Science:

• Hepatocellular carcinoma (HCC) research
• Molecular targeted therapy
• Drug resistance mechanisms

Background:

• Acquired resistance to tyrosine kinase inhibitors (TKIs) is a major obstacle in hepatocellular carcinoma (HCC) treatment.
• Identifying novel therapeutic strategies to overcome or delay TKI resistance in HCC is clinically urgent.

Purpose of the Study:

• To identify new therapeutics that can overcome sorafenib resistance in HCC.
• To elucidate the underlying mechanisms by which lefamulin overcomes sorafenib resistance in HCC.

Main Methods:

• Utilized HCC cell lines, cell line-derived xenograft (CDX), and hydrodynamic injection mouse models to evaluate lefamulin's efficacy.
• Investigated lefamulin's molecular mechanism, including protein binding, acetylation interference, and downstream transcriptional effects on mitochondrial function.
• Analyzed clinical data to correlate ILF3 and MRPL12 expression with patient survival and targeted therapy outcomes.

Main Results:

• A US Food and Drug Administration (FDA)-approved antibiotic, lefamulin, demonstrated efficacy in overcoming sorafenib resistance in preclinical HCC models.
• Lefamulin was shown to target interleukin enhancer-binding factor 3 (ILF3), impairing mitochondrial function and increasing HCC cell susceptibility to sorafenib.
• The drug directly binds ILF3, inhibiting GCN5 and CBP-mediated acetylation, disrupting ILF3's transcriptional regulation of mitochondrial ribosomal protein L12 (MRPL12) and mitochondrial biogenesis.

Conclusions:

• High ILF3 or MRPL12 expression in HCC correlates with poor survival and reduced response to targeted therapies.
• ILF3 emerges as a promising therapeutic target for overcoming TKI resistance in HCC.
• Lefamulin presents a potential novel combination therapy strategy for HCC, particularly with sorafenib and regorafenib.