ArticleCancer science2013
Heregulin induces resistance to lapatinib-mediated growth inhibition of HER2-amplified cancer cells.
Article in Cancer science, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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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.
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Who cites it
30 citing papers in PubMed, 38 citations in OpenAlex.
- Trial
- Acquired resistance of cancer therapies: Mechanisms and perspectives.Chinese medical journal · 2026Review
- Review
- HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments.Cancers · 2024Review
- Lapatinib-induced enhancement of mitochondrial respiration in HER2-positive SK-BR-3 cells: mechanism revealed by analysis of proteomic but not transcriptomic data.Frontiers in molecular biosciences · 2024Article
- Review
- Clinical characteristics and treatment outcomes of HER2 mutation and HER2 fusion in 22 patients with advanced breast cancer.Thoracic cancer · 2023Article
- Review
- Inactivating Amplified HER2: Challenges, Dilemmas, and Future Directions.Cancer research · 2022Article
- Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling.Cell reports · 2022Article
- The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein.Pharmacological reviews · 2022Review
- Pim1 Kinase Inhibitors Exert Anti-Cancer Activity Against HER2-Positive Breast Cancer Cells Through Downregulation of HER2.Frontiers in pharmacology · 2021Article
- Neuregulins in Neurodegenerative Diseases.Frontiers in aging neuroscience · 2021Article
- HER2 splice variants in breast cancer: investigating their impact on diagnosis and treatment outcomes.Oncotarget · 2020Review
- The role of ErbB4 in cancer.Cellular oncology (Dordrecht, Netherlands) · 2020Review
- Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer.Cancer drug resistance (Alhambra, Calif.) · 2020Article
- Clinicopathological and prognostic correlations of HER3 expression and its degradation regulators, NEDD4-1 and NRDP1, in primary breast cancer.BMC cancer · 2018Article
- The HER4-YAP1 axis promotes trastuzumab resistance in HER2-positive gastric cancer by inducing epithelial and mesenchymal transition.Oncogene · 2018Article
- Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2018Article
- Review
Corrections and comments
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 20% of gastric and gastroesophageal junction cancers in the United States and European Union. Lapatinib, a dual HER2 and epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated clinical efficacy in HER2-amplified cancer cells. However, several studies have shown that some cytokines can mediate resistance to lapatinib using their receptor tyrosine kinase (RTK) pathways. One of these, Heregulin1 (HRG1), can confer resistance to lapatinib-mediated growth inhibition in HER2-amplified breast cancer cells, but the underlying mechanisms remain unknown. Here, we investigated whether and how HRG1 causes resistance to lapatinib in gastric and gastroesophageal junction cancers in vitro. HER2-amplified gastric and gastroesophageal junction cancer cell lines were highly sensitive to lapatinib. Exposure to HRG1 together with lapatinib rescued cells from lapatinib-induced cell cycle arrest and apoptosis. Downregulation of HER3 with siRNA in the presence of HRG1 re-sensitized HER2-amplified cancer cells to lapatinib. Immunoblotting analysis indicated that HRG1 re-activated HER3 and AKT in the presence of lapatinib, which persisted for at least 72 h. Activation of HER3 and downstream AKT was mediated by residual activity of HER2. HRG1-mediated resistance could be reduced by PI3K/mTOR inhibitors or by complete inhibition of HER2. Thus, we conclude that HRG1 mediates resistance to lapatinib through HER3 and AKT activation, and that this depends on residual HER2 activity. Lapatinib in combination with anti-PI3K therapies or more potent HER2 inhibitors would improve the efficacy and avoid the emergence of resistant cells.
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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.