Related Experiment Video
Updated: Oct 9, 2025
Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
Published on: June 17, 2022
DIA-Based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid
Wei Liu1, Yaoting Sun2, Weigang Ge3
1Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning, China; Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Omics Research Institute, Westlake Omics (Hangzhou) Biotechnology Co, Ltd, Hangzhou, China.
Abstract:
Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia. To understand the underlying resistance mechanisms in response to imatinib mesylate (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for 2 months to generate derivative cells with mild, intermediate, and severe resistance to the drugs as defined by their increasing resistance index. PulseDIA-based (DIA [data-independent acquisition]) quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7082 proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin signaling pathway was found to be significantly enriched in both ADR-resistant and IMA-resistant K562 cells. In particular, isocitrate dehydrogenase (NADP(+)) 2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated isocitrate dehydrogenase (NADP(+)) 2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.
Insights
Drug resistance in chronic myeloid leukemia (CML) can be overcome by targeting Isocitrate Dehydrogenase 2. Inhibiting this enzyme reversed resistance to imatinib mesylate and adriamycin in K562 cells.
Area of Science:
- Biochemistry
- Oncology
- Proteomics
Background:
- Drug resistance is a major challenge in treating chronic myeloid leukemia (CML).
- Understanding resistance mechanisms to imatinib mesylate (IMA) and adriamycin (ADR) is crucial for developing effective therapies.
Purpose of the Study:
- To investigate proteome alterations in K562 cells resistant to IMA and ADR.
- To identify potential therapeutic targets for overcoming drug resistance in CML.
Main Methods:
- Generation of drug-resistant K562 cell lines (mild, intermediate, severe) through prolonged exposure to IMA or ADR.
- Quantitative proteomics using Pulse Data-independent Acquisition (DIA) to analyze proteome changes.
- Utilized four DIA software tools (OpenSWATH, Spectronaut, DIA-NN, EncyclopeDIA) for data analysis.
Main Results:
- Identified and quantified 7082 proteins from 98,232 peptides.
- The Sirtuin signaling pathway was significantly enriched in both ADR-resistant and IMA-resistant cells.
- Isocitrate dehydrogenase (NADP(+)) 2 (IDH2) was identified as a potential drug target associated with drug resistance.
Conclusions:
- IDH2 plays a role in acquired resistance to IMA and ADR in K562 cells.
- Inhibition of IDH2 using antagonist AGI-6780 successfully reversed drug resistance.
- IDH2 represents a promising therapeutic target to overcome drug resistance in CML treatment.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...