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Determination of the Proteomic Response to Lapatinib Treatment using a comprehensive and reproducible
Kathleen O'Connell1, Jun Li2, Frank Engler2
1Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC.
Abstract:
Lapatinib, a small molecule tyrosine kinase inhibitor is currently used in the treatment of HER2-positive breast cancer. The aim of this study was to further understanding of lapatinib response for the development of novel treatment lapatinib-focussed treatment strategies. HER2-overexpressing SKBR3 breast cancer cells were treated with lapatinib for 12 hours and the resultant proteome analyzed by a comprehensive ion-current-based LC-MS strategy. Among the 1224 unique protein identified from SKBR3 cell lysates, 67 showed a significant change in protein abundance in response to lapatinib. Of these, CENPE a centromeric protein with increased abundance, was chosen for further validation. Knockdown and inhibition of CENPE demonstrated that CENPE enhances SKBR3 cell survival in the presence of lapatinib. Based on this study, CENPE inhibitors may warrant further investigation for use in combination with lapatinib.
Insights
Lapatinib treats HER2-positive breast cancer. This study found that inhibiting CENPE enhances lapatinib effectiveness by improving cancer cell survival, suggesting combination therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lapatinib is a tyrosine kinase inhibitor used for HER2-positive breast cancer.
- Understanding lapatinib's molecular mechanisms is crucial for developing improved treatment strategies.
Purpose of the Study:
- To investigate the proteomic changes in response to lapatinib in HER2-overexpressing breast cancer cells.
- To identify novel therapeutic targets for enhancing lapatinib efficacy.
Main Methods:
- Utilized a comprehensive liquid chromatography-mass spectrometry (LC-MS) approach to analyze the proteome of SKBR3 cells treated with lapatinib.
- Quantified protein abundance changes in response to lapatinib treatment.
- Validated the role of CENPE through knockdown and inhibition experiments.
Main Results:
- Identified 1224 unique proteins, with 67 showing significant abundance changes upon lapatinib treatment.
- Observed increased abundance of CENPE, a centromeric protein.
- Demonstrated that CENPE knockdown or inhibition enhances SKBR3 cell survival in the presence of lapatinib.
Conclusions:
- CENPE plays a role in promoting cancer cell survival under lapatinib treatment.
- Targeting CENPE in combination with lapatinib may represent a promising therapeutic strategy for HER2-positive breast cancer.
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