Abstract
BackgroundKIT 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.ResultsIn 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.ConclusionsOur 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.
Highlights
KIT mutations are the predominant driver mutations in gastrointestinal stromal tumors (GISTs), and targeted therapy against KIT has improved treatment outcome dramatically
Secondary mutation increases the ligand‐independent activation of KIT Mutations of KIT in primary GISTs usually occur in exon 9, 11 and 13 while secondary mutations of KIT are usually identified in exon 13, 14, 17 and 18 in relapsed GISTs after treatment with Imatinib
The deletion of W557K558 (W557K558del) in exon 11 and duplication of A502Y503 (A502Y503dup) in exon 9 are the most often occurred primary mutations of KIT, they respectively account for 11.3% and 9.7% of primary KIT mutations in GISTs (Table 1) GISTs carrying KIT mutations usually respond well to Imatinib, some tumors gain drug-resistant secondary mutation of KIT leading to relapse and treatment failure
Summary
KIT mutations are the predominant driver mutations in gastrointestinal stromal tumors (GISTs), and targeted therapy against KIT has improved treatment outcome dramatically. Relapse of low risk primary GISTs after surgery is not very often, targeted therapy with Imatinib is necessary for the treatment of primary GISTs with high risk and metastatic GISTs. Imatinib is a small molecular inhibitor that can inhibit the activation of wild-type KIT and most KIT mutations identified in GISTs, and others such as PDGFRA and BCR-Abl. Treatment of GISTs with Imatinib can prolong the survival of GISTs patients for around 5 years in average [13], but most tumors will develop drug resistance by gaining a drug-resistant secondary mutation of KIT [14,15,16,17,18,19] or activation of alternative signaling pathways [20,21,22,23], leading to treatment failure. Compared with Imatinib which can prolong patient survival for years, the benefit from both Sunitinib and Regorafenib is very limited, they can prolong patient survival for only few months [24, 25]
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