Combination of pimitespib (TAS-116) with sunitinib is an effective therapy for imatinib-resistant gastrointestinal stromal tumors.
Humans
Animals
Mice
Imatinib Mesylate
/ pharmacology
Sunitinib
/ pharmacology
Gastrointestinal Stromal Tumors
/ pathology
Vascular Endothelial Growth Factor A
Piperazines
/ pharmacology
Pyrimidines
Drug Resistance, Neoplasm
Antineoplastic Agents
/ therapeutic use
Proto-Oncogene Proteins c-kit
/ metabolism
Protein Kinase Inhibitors
/ pharmacology
GISTs
angiogenesis
imatinib-resistant
pimitespib
sunitinib
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 06 2023
15 06 2023
Historique:
revised:
29
12
2022
received:
21
11
2022
accepted:
26
01
2023
medline:
17
4
2023
pubmed:
9
2
2023
entrez:
8
2
2023
Statut:
ppublish
Résumé
Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.
Substances chimiques
Imatinib Mesylate
8A1O1M485B
Sunitinib
V99T50803M
TAS-116
0
Vascular Endothelial Growth Factor A
0
Piperazines
0
Pyrimidines
0
Antineoplastic Agents
0
Proto-Oncogene Proteins c-kit
EC 2.7.10.1
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2580-2593Informations de copyright
© 2023 UICC.
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