Integrative proteo-genomic profiling uncovers key biomarkers of lapatinib resistance in HER2-positive breast cancer
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Updated: Jan 6, 2026
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
J Steggall1, V Rajeeve2, N Al-Subaie3
1Department of Molecular and Biomedical Sciences, City St George's, University of London, London, UK.
Introduction:
Drug resistance is a major obstacle to the long-term effectiveness of cancer therapies. Approximately 70% of breast cancer patients relapse after 5 years of treatment, and the lack of biomarkers associated with drug resistance translates to poor prognosis in the clinic. Previous research has utilised omics approaches to uncover biomarkers driving drug resistance, with a strong emphasis on genetic mutations.
Methods:
Here, we identified a nine-marker signature associated with resistance to lapatinib in a HER2-positive breast cancer model using a target discovery approach by employing an integrative multi-omics strategy, combining ATAC-seq, RNA-seq and proteomics.
Results:
We found that seven markers in the drug resistance-signature had not been previously found to be implicated in HER2-positive breast cancer, some of which we further validated using an additional lung cancer model. We counterintuitively found that drug-resistant cells have restrictive chromatin accessibility with reduced gene expression associated with limited total proteome changes. However, upon closer look, we identified that the drug resistance-signature had increased chromatin accessibility near the transcriptional start sites of those seven markers and was highly differentially expressed across the three datasets. Our data show that despite the overall transcriptional and proteomic landscape showing limited changes, there are several markers that are highly expressed, which correlate with increased anchorage-independent and invasive phenotype in vitro in lapatinib-resistant cells compared to cancer cells.
Conclusions:
Our results demonstrate that disease aggressiveness can be related to reduced chromatin and gene expression dynamics. We anticipate that the resistant signature identified here using an integrative target discovery approach can be applied to complex, more representative models and validated before they can be targeted by suitable therapeutic agents.
Insights
A new nine-marker signature for lapatinib resistance in HER2-positive breast cancer was identified. This signature, linked to increased invasiveness, offers potential therapeutic targets for overcoming drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Drug resistance significantly limits cancer therapy effectiveness, with high relapse rates in breast cancer patients.
- Lack of drug resistance biomarkers leads to poor clinical prognosis.
- Previous research focused on genetic mutations to identify drug resistance drivers.
Purpose of the Study:
- To identify novel biomarkers associated with lapatinib resistance in HER2-positive breast cancer.
- To investigate the role of chromatin accessibility and gene expression in drug resistance.
- To discover a nine-marker signature for predicting and potentially targeting drug resistance.
Main Methods:
- Utilized an integrative multi-omics strategy combining ATAC-seq, RNA-seq, and proteomics.
- Employed a target discovery approach to identify a nine-marker resistance signature.
- Validated findings in both HER2-positive breast cancer and lung cancer models.
Main Results:
- Identified a nine-marker signature associated with lapatinib resistance.
- Seven markers in the signature were novel to HER2-positive breast cancer.
- Drug-resistant cells showed restricted chromatin accessibility but increased accessibility near key marker TSS.
- Resistance signature markers were highly differentially expressed and correlated with increased invasiveness in vitro.
Conclusions:
- Disease aggressiveness may be linked to reduced chromatin and gene expression dynamics.
- The identified resistance signature can be applied to more complex models for validation.
- This signature holds potential for developing targeted therapeutic agents against drug resistance.
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