ArticleBMC cancer2018
Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL.
Article in BMC cancer, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01485926 (A Phase II Neo-adjuvant Study Assessing TCH), which is not on this map. Cited by 13 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
A Phase II Neo-adjuvant Study Assessing TCH (Docetaxel, Carboplatin and Trastuzumab) and TCHL (Docetaxel, Carboplatin, Trastuzumab and Lapatinib) in HER-2 Positive Breast Cancer Patients.
Who cites it
13 citing papers in PubMed, 30 citations in OpenAlex.
- Repurposing Lapatinib and Tucatinib as Dual Inhibitors of Bcl-2 and TYMS in Breast Cancer: Insights from Transcriptomic, Computational and Cellular Assays.Applied biochemistry and biotechnology · 2026Article
- Emerging opportunities to treat drug-resistant breast cancer: Discovery of novel small-molecule inhibitors against different targets.Frontiers in pharmacology · 2025Review
- HER2-targeted therapies for HER2-positive early-stage breast cancer: present and future.Frontiers in pharmacology · 2024Review
- Role and regulation of FOXO3a: new insights into breast cancer therapy.Frontiers in pharmacology · 2024Review
- Therapeutic potential of TRPM8 channels in cancer treatment.Frontiers in pharmacology · 2023Review
- Article
- Partial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient withOncoTargets and therapy · 2021Article
- Drug resistance gene expression and chemotherapy sensitivity detection in Chinese women with different molecular subtypes of breast cancer.Cancer biology & medicine · 2020Article
- Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: opportunities to overcome a difficult problem.Cancer drug resistance (Alhambra, Calif.) · 2020Review
- Interplay Between Autophagy and Wnt/β-Catenin Signaling in Cancer: Therapeutic Potential Through Drug Repositioning.Frontiers in oncology · 2020Review
- Coptisine from Coptis chinensis exerts diverse beneficial properties: A concise review.Journal of cellular and molecular medicine · 2019Review
- c-FLIP, a Novel Biomarker for Cancer Prognosis, Immunosuppression, Alzheimer's Disease, Chronic Obstructive Pulmonary Disease (COPD), and a Rationale Therapeutic Target.Biomarkers journal · 2019Article
- AK4 Promotes the Progression of HER2-Positive Breast Cancer by Facilitating Cell Proliferation and Invasion.Disease markers · 2019Article
Corrections and comments
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Authors and funding
22 authors at 10 institutions in 3 countries.
Funding
Abstract
backgroundLapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells.
methodsWe examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer.
resultsIn this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL-2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells.
conclusionsOur findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies.
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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.