Related Experiment Video
Updated: Sep 30, 2025
09:58
Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
Published on: December 9, 2016
13.9K
Mitochondrial Dysfunction Is a Driver of SP-2509 Drug Resistance in Ewing Sarcoma
E John Tokarsky1, Jesse C Crow1, Lillian M Guenther2
1Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
Molecular Cancer Research : MCR
|March 17, 2022
Summary
Mitochondrial dysfunction can cause resistance to lysine-specific demethylase-1 (LSD1) inhibitors in Ewing sarcoma. Combining LSD1 inhibitors with agents that prevent mitochondrial dysfunction may improve patient outcomes.
Area of Science:
- Oncology
- Epigenetics
- Mitochondrial Biology
Background:
- Ewing sarcoma is an aggressive pediatric cancer driven by the EWS/FLI oncoprotein and characterized by epigenetic alterations.
- Lysine-specific demethylase-1 (LSD1) inhibitors are a novel therapeutic strategy targeting these epigenetic changes and are in early clinical trials.
- Therapy resistance is a significant challenge, necessitating the understanding of resistance mechanisms for developing effective combination treatments.
Purpose of the Study:
- To identify genes conferring resistance to the LSD1 inhibitor SP-2509 in Ewing sarcoma using a genome-scale CRISPR-Cas9 screen.
- To investigate the role of mitochondrial function in mediating resistance to LSD1 inhibition.
- To explore potential combination therapies for Ewing sarcoma.
Main Methods:
- Genome-scale CRISPR-Cas9 loss-of-function screening in Ewing sarcoma cell lines.
- Validation of hits using genetic (CRISPR knockout) and chemical approaches (ETC inhibitors, mitochondrial depletion).
- Global transcriptional profiling to assess the impact of mitochondrial dysfunction on oncogenic pathways and drug response.
Main Results:
- Genes essential for mitochondrial electron transport chain (ETC) complexes III and IV function were identified as conferring resistance to SP-2509.
- Disruption of mitochondrial complex III/IV function was shown to impair the EWS/FLI oncogenic program and blunt the response to SP-2509.
- Mitochondrial dysfunction was demonstrated to modulate the efficacy of the LSD1 inhibitor SP-2509.
Conclusions:
- Mitochondrial dysfunction plays a critical role in resistance to LSD1 inhibitors in Ewing sarcoma.
- Combination strategies involving LSD1 inhibitors and agents targeting mitochondrial function may offer a promising therapeutic approach for Ewing sarcoma patients.
- Further research into the interplay between epigenetic regulation and mitochondrial metabolism in cancer is warranted.
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
15.2K
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
15.2K
02:56Treatment Resistant Cancers
3.4K
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.4K