A novel treatment strategy for lapatinib resistance in a subset of HER2-amplified gastric cancer

Autor: Hamin Lee, Gang Ning, Mayerlin Silva, Charles Lee, Qihui Zhu, Chengsheng Zhang, Michael Michaud, Jee Young Kwon, Yun Suhk Suh, Leigh Maher, Wonyoung Kang
Rok vydání: 2021
Předmět:
Cancer Research
Receptor
ErbB-2
medicine.medical_treatment
Apoptosis
Mice
SCID
Tyrosine-kinase inhibitor
Targeted therapy
Mice
Mice
Inbred NOD
Antineoplastic Combined Chemotherapy Protocols
Tumor Cells
Cultured
skin and connective tissue diseases
RC254-282
Trametinib
HER2 amplification
biology
MEK inhibitor
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Gene Expression Regulation
Neoplastic
Oncology
Female
medicine.drug
Lapatinib resistance
Pyridones
medicine.drug_class
Pyrimidinones
Lapatinib
CRISPR/Cas9 screening
And MAPK pathway
Stomach Neoplasms
Biomarkers
Tumor
Genetics
medicine
Animals
Humans
PTEN
PI3K/AKT/mTOR pathway
Cell Proliferation
business.industry
Gene Expression Profiling
Research
Cancer
medicine.disease
Xenograft Model Antitumor Assays
PI3K pathway
Pyrimidines
Drug Resistance
Neoplasm
Quinazolines
biology.protein
Cancer research
Gastric cancer
business
Zdroj: BMC Cancer
BMC Cancer, Vol 21, Iss 1, Pp 1-17 (2021)
ISSN: 1471-2407
Popis: Background Gastric 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. Methods We 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. Results We 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. Conclusions Our 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.
Databáze: OpenAIRE
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