ArticleCarcinogenesis2019
Lapatinib-induced annexin A6 upregulation as an adaptive response of triple-negative breast cancer cells to EGFR tyrosine kinase inhibitors.
Article in Carcinogenesis, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Biomarkers of tumor invasiveness in proteomics (Review).International journal of oncology · 2020Pooled it
- Sequential invasion assays identify carbonic anhydrase IX as a driver of invasiveness in epithelial triple-negative breast cancer cells.American journal of physiology. Cell physiology · 2026Article
- Article
- Contribution of Mesenchymal-like and Epithelial Cellular Subsets to Chemotherapy Resistance in Triple-Negative Breast Cancer.International journal of molecular sciences · 2026Article
- Contribution of Mesenchymal-like and Epithelial Cellular Subsets to Chemotherapy Resistance in Triple-Negative Breast Cancer.bioRxiv : the preprint server for biology · 2025Article
- Tailored therapies for triple-negative breast cancer: current landscape and future perceptions.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Breaking Barriers in Breast Cancer: Multi-Targeted Therapeutic Insights.Mini reviews in medicinal chemistry · 2025Review
- PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway.Cell death & disease · 2024Article
- ANXA6: a key molecular player in cancer progression and drug resistance.Discover oncology · 2023Review
- Article
- Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance.International journal of molecular sciences · 2022Review
- Article
- Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions.Scientific reports · 2022Article
- Heat Shock Protein 90 (HSP90) Inhibitors as Anticancer Medicines: A Review on the Computer-Aided Drug Discovery Approaches over the Past Five Years.Computational and mathematical methods in medicine · 2022Review
- Pathobiological functions and clinical implications of annexin dysregulation in human cancers.Frontiers in cell and developmental biology · 2022Review
- Exosomal annexin A6 induces gemcitabine resistance by inhibiting ubiquitination and degradation of EGFR in triple-negative breast cancer.Cell death & disease · 2021Article
- Annexin Animal Models-From Fundamental Principles to Translational Research.International journal of molecular sciences · 2021Review
- Tyrosine Kinase Inhibitors Are Promising Therapeutic Tools for Cats with HER2-Positive Mammary Carcinoma.Pharmaceutics · 2021Article
- Breast Cancer Stem Cell-Derived ANXA6-Containing Exosomes Sustain Paclitaxel Resistance and Cancer Aggressiveness in Breast Cancer.Frontiers in cell and developmental biology · 2021Article
- Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
The epidermal growth factor receptor (EGFR) is a major oncogene in triple-negative breast cancer (TNBC), but the use of EGFR-targeted tyrosine kinase inhibitors (TKI) and therapeutic monoclonal antibodies is associated with poor response and acquired resistance. Understanding the basis for the acquired resistance to these drugs and identifying biomarkers to monitor the ensuing resistance remain a major challenge. We previously showed that reduced expression of annexin A6 (AnxA6), a calcium-dependent membrane-binding tumor suppressor, not only promoted the internalization and degradation of activated EGFR but also sensitized TNBC cells to EGFR-TKIs. Here, we demonstrate that prolong (>3 days) treatment of AnxA6-low TNBC cells with lapatinib led to AnxA6 upregulation and accumulation of cholesterol in late endosomes. Basal extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation was EGFR independent and significantly higher in lapatinib-resistant MDA-MB-468 (LAP-R) cells. These cells were more sensitive to cholesterol depletion than untreated control cells. Inhibition of lapatinib-induced upregulation of AnxA6 by RNA interference (A6sh) or withdrawal lapatinib from LAP-R cells not only reversed the accumulation of cholesterol in late endosomes but also led to enrichment of plasma membranes with cholesterol, restored EGFR-dependent activation of ERK1/2 and sensitized the cells to lapatinib. These data suggest that lapatinib-induced AnxA6 expression and accumulation of cholesterol in late endosomes constitute an adaptive mechanism for EGFR-expressing TNBC cells to overcome prolong treatment with EGFR-targeted TKIs and can be exploited as an option to inhibit and/or monitor the frequently observed acquired resistance to these drugs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.