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

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Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib. / Zhu, Guangrong; Shi, Jun; Zhang, Shaoting; Guo, Yue; Huang, Ling; Zhao, Hui; Jiang, Yideng; Sun, Jianmin.

I: Cell and Bioscience, Vol. 10, Nr. 1, 16, 12.02.2020.

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Zhu, Guangrong ; Shi, Jun ; Zhang, Shaoting ; Guo, Yue ; Huang, Ling ; Zhao, Hui ; Jiang, Yideng ; Sun, Jianmin. / Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib. I: Cell and Bioscience. 2020 ; Vol. 10, Nr. 1.

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TY - JOUR

T1 - Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib

AU - Zhu, Guangrong

AU - Shi, Jun

AU - Zhang, Shaoting

AU - Guo, Yue

AU - Huang, Ling

AU - Zhao, Hui

AU - Jiang, Yideng

AU - Sun, Jianmin

PY - 2020/2/12

Y1 - 2020/2/12

N2 - 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.

AB - 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.

KW - Drug resistance

KW - GISTs

KW - Imatinib

KW - KIT

KW - PI3 kinase

UR - http://www.scopus.com/inward/record.url?scp=85081255766&partnerID=8YFLogxK

U2 - 10.1186/s13578-020-0377-9

DO - 10.1186/s13578-020-0377-9

M3 - Article

C2 - 32082541

AN - SCOPUS:85081255766

VL - 10

JO - Cell and Bioscience

JF - Cell and Bioscience

SN - 2045-3701

IS - 1

M1 - 16

ER -