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Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Posted: Tuesday, June 13, 2023
Findings presented at the European Hematology Association (EHA) 2023 Hybrid Congress (Abstract S185) demonstrate that multiple myeloma cells are required to use oxidative phosphorylation to overcome DNA damage, indicating the mechanisms surrounding oxidative phosphorylation may prove to be a potential therapeutic target in the future. “DNA damage resistance is a major barrier to effective DNA-damaging anticancer therapy in multiple myeloma,” said study author Natthakan Thongon, PhD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues. “Given that metabolic reprogramming is a hallmark of cancer progression, further studies will clarify whether therapeutically targeting DNA2 has a broad spectrum of anticancer applications.”
The authors induced DNA damage in five different multiple myeloma cell lines by knocking down expression of interleukin enhancer binding factor 2 (ILF2). A total of 300 antisense oligonucleotides were screened for ILF2 depletion activity, and the most effective were used for functional validation studies. However, the authors reported that after 3 weeks, multiple myeloma cell lines developed resistance to ILF2 depletion. This led the investigators to use RNA sequencing to identify proteins that overcame the resistance. Numerous sequencing and microscopy techniques were used to understand the mechanisms of DNA damage resistance.
Sequencing analysis demonstrated that ILF2 depletion–resistant cells upregulated genes within the oxidative phosphorylation pathway and genes associated with DNA repair. Using CRISPR/Cas9 screening, the researchers identified DNA2, an oxidative phosphorylation inhibitor, as more effective at helping multiple myeloma cells overcome ILF2 depletion. Employing the DNA2 inhibitor NSC105808 enhanced apoptosis in resistant cells and impaired metabolism. The researchers emphasized that this result seems to indicate that DNA2 may counter oxidative DNA damage and support mitochondrial respiration in cells with high mitochondrial demand—such as multiple myeloma cells.
Disclosure: Disclosure information for the study authors was not provided.
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