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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 and Sun, Jianmin LU (2020) In Cell and Bioscience 10(1).
Abstract

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... (More)

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.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Drug resistance, GISTs, Imatinib, KIT, PI3 kinase
in
Cell and Bioscience
volume
10
issue
1
article number
16
publisher
BioMed Central (BMC)
external identifiers
  • pmid:32082541
  • scopus:85081255766
ISSN
2045-3701
DOI
10.1186/s13578-020-0377-9
language
English
LU publication?
yes
id
4f335809-4b8a-4d22-87ef-0cb80b22dcc1
date added to LUP
2020-04-03 15:08:27
date last changed
2020-04-04 03:00:05
@article{4f335809-4b8a-4d22-87ef-0cb80b22dcc1,
  abstract     = {<p>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.</p>},
  author       = {Zhu, Guangrong and Shi, Jun and Zhang, Shaoting and Guo, Yue and Huang, Ling and Zhao, Hui and Jiang, Yideng and Sun, Jianmin},
  issn         = {2045-3701},
  language     = {eng},
  month        = {02},
  number       = {1},
  publisher    = {BioMed Central (BMC)},
  series       = {Cell and Bioscience},
  title        = {Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib},
  url          = {http://dx.doi.org/10.1186/s13578-020-0377-9},
  doi          = {10.1186/s13578-020-0377-9},
  volume       = {10},
  year         = {2020},
}