ArticlePloS one2009
Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2.
Article in PloS one, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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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
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 115 citations in OpenAlex.
- Pooled it
- Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study.British journal of cancer · 2017Trial
- A Phase II Biomarker-Embedded Study of Lapatinib plus Capecitabine as First-line Therapy in Patients with Advanced or Metastatic Gastric Cancer.Molecular cancer therapeutics · 2016Trial
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- An MIEN1-based hexamer peptide (LA3IK) inhibits EGF-driven oncogenic signaling in prostate cancer by disrupting EGFR-ERBB2 heterodimerization.Scientific reports · 2026Article
- Restoration of Osimertinib sensitivity in lung cancer through BRD4 inhibitor-mediated depalmitoylation of mutant EGFR via APT1.NPJ precision oncology · 2025Article
- Emerging Concepts in Immuno-Oncology: Insights from Natural Language Processing-Driven Co-Occurrence Analysis.ACS omega · 2025Review
- Targeting exon mutations in NSCLC: clinical insights into LAG-3, TIM-3 pathways, and advances in fourth-generation EGFR-TKIs.Medical oncology (Northwood, London, England) · 2025Review
- Understanding the Mechanisms of Chemotherapy-Related Cardiotoxicity Employing hiPSC-Derived Cardiomyocyte Models for Drug Screening and the Identification of Genetic and Epigenetic Variants.International journal of molecular sciences · 2025Review
- Targeting AFP-RARβ complex formation: a potential strategy for treating AFP-positive hepatocellular carcinoma.Molecular diversity · 2025Article
- Proteomic Assessment of SKBR3/HER2+ Breast Cancer Cellular Response to Lapatinib and Investigational Ipatasertib Kinase Inhibitors.bioRxiv : the preprint server for biology · 2024Article
- Proteomic assessment of SKBR3/HER2+ breast cancer cellular response to Lapatinib and investigational Ipatasertib kinase inhibitors.Frontiers in pharmacology · 2024Article
- 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
- Novel 2-Sulfanylquinazolin-4(3Molecules (Basel, Switzerland) · 2023Article
- High-throughput computational screening andOncology research · 2023Article
- EGFR blocker lapatinib inhibits the synthesis of matrix metalloproteinases from synovial fibroblasts.Turkish journal of medical sciences · 2022Article
- The role of epigenetic modifications in drug resistance and treatment of breast cancer.Cellular & molecular biology letters · 2022Review
- Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism.Molecules (Basel, Switzerland) · 2021Review
- Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth.Oncogene · 2020Article
- PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer.Scientific reports · 2020Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundEpidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been shown to exert a synergistic antitumor effect when combined with fluoropyrimidine. This synergy may be attributable to the downregulation of thymidylate synthase (TS), which is frequently overexpressed in fluoropyrimidine-resistant cancer cells. However, the molecular mechanism underlying the downregulation of TS has yet to be clearly elucidated. METHODOLOGY AND PRINCIPAL
findingsIn this study, we demonstrate that lapatinib, a dual TKI of EGFR and HER2 downregulates TS via inhibition of the nuclear translocation of EGFR and HER2. From our cDNA microarray experiments, we determined that a variety of nucleotide synthesis-related genes, including TS, were downregulated with lapatinib, and this was apparent in HER2-amplified cells. Targeted and pharmacologic inhibition assays confirmed that the dual inhibition of EGFR and HER2 is required for the more effective reduction of TS as compared to what was observed with gefitinib or trasutuzumab alone. Additionally, we determined that co-transfected EGFR and HER2 activate the TS gene promoter more profoundly than do either EGFR or HER2 alone. The translocation of EGFR and HER2 into the nucleus and the subsequent activation of the TS promoter were inhibited by lapatinib. CONCLUSIONS AND SIGNIFICANCE: These results demonstrate that lapatinib inhibits the nuclear translocation of EGFR and HER2 and downregulates TS, thus sensitizing cancer cells to fluoropyrimidine.
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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.