Identification of a Mitochondrial DNA Polymerase Affecting Cardiotoxicity of Sunitinib Using a Genome-Wide Screening on S. pombe Deletion Library

Area of Science:

• Molecular Biology
• Genetics
• Pharmacology

Background:

• Drug toxicity, particularly cardiotoxicity induced by anticancer drugs like sunitinib, poses a significant challenge in drug R&D.
• Identifying drug targets genome-wide is crucial for understanding and mitigating drug toxicity.
• Sunitinib, a tyrosine kinase inhibitor, is known to cause cardiotoxicity, necessitating investigation into its molecular mechanisms.

Purpose of the Study:

• To elucidate the molecular insights into sunitinib-induced cardiotoxicity at the genome level.
• To identify potential drug targets responsible for sunitinib's cardiotoxicity using a genome-wide screening approach.

Main Methods:

• Utilized genome-wide drug target screening technology (GPScreen) in fission yeast (Schizosaccharomyces pombe).
• Employed drug-induced haploinsufficiency (DIH) assay across a S. pombe genome-wide deletion library.
• Investigated the role of the identified target by knocking down its human ortholog in human cells.

Main Results:

• Identified mitochondrial DNA polymerase (POG1) as a key target of sunitinib.
• Sunitinib induced more severe cytotoxicity and mitochondrial damage in POG1-deleted heterozygous mutants compared to wild type.
• Knockdown of the human ortholog (POLG) significantly increased sunitinib cytotoxicity in human cells.
• Sunitinib decreased POLG mRNA and protein levels, exacerbating mitochondrial damage.

Conclusions:

• POLG plays a crucial role in sunitinib-induced cardiotoxicity by being a target of sunitinib's expressional pathway.
• Genome-wide drug target screening using GPScreen is effective for discovering drug toxicity targets and understanding molecular mechanisms.
• This approach aids in understanding drug toxicity and developing strategies to mitigate adverse effects.