Our study has validated the approach and revealed the potential molecular mechanisms for the treatment of subsets of GC cases: loss-of-function mutation of CSK or PTEN causes resistance to lapatinib in HER2-amplified GC cells via hyperactivation of PI3K and MAPK pathways, which can be overcome by applying drug combination of lapatinib, PI3K and MAPK pathway inhibitors. Here, CSK is linked to gastric cancer.