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Investigation on acquired palbociclib resistance by LC-MS based multi-omics analysis
Zhichao Xue1, Jiaming Zeng2, Xinchi Yin1
1Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China.
Frontiers in Molecular Biosciences
|February 6, 2023
Summary
Palbociclib resistance in cancer involves altered cell metabolism and elevated N-glycosylation. Combining palbociclib with COX-1 or N-glycosylation inhibitors resensitizes resistant cells, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Palbociclib, a CDK4/6 inhibitor, is crucial for treating various cancers but faces inevitable drug resistance.
- Understanding palbociclib resistance mechanisms is vital for developing effective cancer therapies.
Purpose of the Study:
- To investigate the molecular mechanisms underlying acquired palbociclib resistance using multi-omics analysis.
- To identify potential therapeutic targets and strategies to overcome palbociclib resistance.
Main Methods:
- In vitro training of palbociclib-resistant cancer cells.
- LC-MS based multi-omics analysis: proteomics, metabolomics, and glycoproteomics.
- Integration of multi-omics data to identify resistance-associated pathways and proteins.
Main Results:
- Proteomic analysis revealed upregulated metabolic pathways (carbohydrates, lipids, DNA, glucose, amino acids) and overexpression of COX-1 and NDUFB8 in resistant cells.
- Metabolomics identified the N-glycan biosynthesis pathway, and glycoproteomics showed elevated global glycosylation.
- Integrated analysis identified low-abundance glycosylated proteins involved in cell migration and glycoprotein metabolism, suggesting a role for N-glycosylation in resistance.
Conclusions:
- Acquired palbociclib resistance is associated with metabolic reprogramming and altered N-glycosylation.
- Targeting COX-1 or N-glycosylation pathways, in combination with palbociclib, can overcome drug resistance.
- The integrated multi-omics approach is effective for discovering drug resistance mechanisms and guiding new drug development.
