ArticleBMC cancer2021
A novel treatment strategy for lapatinib resistance in a subset of HER2-amplified gastric cancer.
Article in BMC cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Bibliometric analysis of tumor marker application in gastric cancer diagnosis from 2019 to 2024.Frontiers in medicine · 2025Pooled it
- MCLRP: enhanced prediction of anticancer drug response through low-rank matrix completion and transcriptomic profiling.BMC biology · 2025Article
- Identification and validation of prognostic genes associated with mitochondrial nuclear genes in gastric cancer.Clinical and experimental medicine · 2025Article
- Identification of an extracellular matrix signature for predicting prognosis and sensitivity to therapy of patients with gastric cancer.Scientific reports · 2025Article
- Article
- HER2-targeted therapies beyond breast cancer - an update.Nature reviews. Clinical oncology · 2024Review
- HER2International journal of oncology · 2024Review
- Targeting PI3K/AKT/mTOR and MAPK Signaling Pathways in Gastric Cancer.International journal of molecular sciences · 2024Review
- Targeted and Immunotherapy Approaches in HER2-Positive Gastric and Gastroesophageal Junction Adenocarcinoma: A New Era.Journal of immunotherapy and precision oncology · 2023Review
- Genome-wide CRISPR/Cas9 screening for drug resistance in tumors.Frontiers in pharmacology · 2023Review
- Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective.Signal transduction and targeted therapy · 2022Review
- The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers.Heliyon · 2022Article
- Olaparib for Chinese metastatic castration-resistant prostate cancer: A real-world study of efficacy and gene predictive analysis.Medical oncology (Northwood, London, England) · 2022Article
- Gastric Cancer Signaling Pathways and Therapeutic Applications.Technology in cancer research & treatmentReview
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundGastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 13-23% of all GC cases and patients with HER2 overexpression exhibit a poor prognosis. Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, is an effective agent to treat HER2-amplified breast cancer but it failed in gastric cancer (GC) clinical trials. However, the molecular mechanism of lapatinib resistance in HER2-amplified GC is not well studied.
methodsWe employed an unbiased, genome-scale screening with pooled CRISPR library on HER2-amplified GC cell lines to identify genes that are associated with resistance to lapatinib. To validate the candidate genes, we applied in vitro and in vivo pharmacological tests to confirm the function of the target genes.
resultsWe found that loss of function of CSK or PTEN conferred lapatinib resistance in HER2-amplified GC cell lines NCI-N87 and OE19, respectively. Moreover, PI3K and MAPK signaling was significantly increased in CSK or PTEN null cells. Furthermore, in vitro and in vivo pharmacological study has shown that lapatinib resistance by the loss of function of CSK or PTEN, could be overcome by lapatinib combined with the PI3K inhibitor copanlisib and MEK inhibitor trametinib.
conclusionsOur study suggests that loss-of-function mutations of CSK and PTEN cause lapatinib resistance by re-activating MAPK and PI3K pathways, and further proved these two pathways are druggable targets. Inhibiting the two pathways synergistically are effective to overcome lapatinib resistance in HER2-amplified GC. This study provides insights for understanding the resistant mechanism of HER2 targeted therapy and novel strategies that may ultimately overcome resistance or limited efficacy of lapatinib treatment for subset of HER2 amplified GC.
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