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.
Highlights
Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide
We demonstrated that the lapatinib resistance involves restoration of the phosphatidylinositol 3 kinase (PI3K)/AKT and Mitogen-activated protein kinase (MAPK) pathways, and that this restoration is induced by the loss of function of either CSK or PTEN
We examined apoptosis induced by lapatinib treatment in CSK- and PTEN-null cells as well as in control cells by measuring caspase-3/7 activation (Caspase-Glo 3/7 assay)
Summary
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. 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. Clinical trial data of HER2-amplified GC have shown that trastuzumab improved overall survival by only 2.7 months, and that lapatinib failed to improve survival in HER2-positive GC patients [9,10,11]. These unsatisfactory results can be attributed to the intrinsic or acquired resistance to HER2-targeted therapy. Further studies are needed to identify the mechanisms of resistance for patients who do not carry those known genomic alterations
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