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Background  KIT mutations are the predominant driver mutations in gastrointestinal stromal tumors (GISTs), and targeted therapy against KIT has improved treatment outcome dramatically. However, gaining secondary mutation of KIT confers drug resistance of GISTs leading to treatment failure.    Results  In this study, we found that secondary mutation of KIT dramatically increases the ligand-independent activation of the receptor and their resistance to the often used KIT inhibitor Imatinib in the treatment of GISTs. PI3 kinase plays essential roles in the cell transformation mediated by the primary mutation of KIT. We found that loss of PI3 kinase association, but not the inhibition of the lipid kinase activity of PI3 kinase, inhibits the ligand-independent activation of secondary mutations of KIT, and increases their sensitivity to Imatinib, and loss of PI3 kinase association inhibits secondary mutations of KIT mediated cell survival and proliferation in vitro. The in vivo assay further showed that the growth of tumors carrying secondary mutations of KIT is more sensitive to Imatinib when PI3 kinase association is blocked while inhibition of the lipid kinase activity of PI3 kinase cannot inhibit tumor growth, indicating that PI3 kinase is important for the drug resistance of secondary mutation of KIT independent of the lipid kinase activity of PI3 kinase.    Conclusions  Our results suggested that PI3 kinase is necessary for the ligand-independent activation of secondary mutations of KIT, and loss of PI3 kinase association improves the sensitivity of secondary mutations to the targeted therapy independent of the lipid kinase activity of PI3 kinase.

Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib