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Updated: Jun 23, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Activity of triptolide against human mast cells harboring the kinase domain mutant KIT
Yanli Jin1, Qi Chen, Xianping Shi
1Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Abstract:
Gain-of-function mutations of the receptor tyrosine kinase KIT can cause systemic mastocytosis (SM) and gastrointestinal stromal tumors. Most of the constitutively active KIT can be inhibited by imatinib; D816V KIT cannot. In this study, we investigated the activity of triptolide, a diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook. f., in cells expressing mutant KIT, including D816V KIT. Imatinib-sensitive HMC-1.1 cells harboring the mutation V560G in the juxtamembrane domain of KIT, imatinib-resistant HMC-1.2 cells harboring both V560G and D816V mutations, and murine P815 cells, were treated with triptolide, and analyzed in terms of growth, apoptosis, and signal transduction. The in vivo antitumor activity was evaluated by using the nude mouse xenograft model. Our results demonstrated that triptolide potently inhibits the growth of both human and murine mast cells harboring not only imatinib-sensitive KIT mutation but also imatinib-resistant D816V KIT. Triptolide markedly inhibited KIT mRNA levels and strikingly reduced the levels of phosphorylated and total Stat3, Akt, and Erk1/2, downstream targets of KIT. Triptolide triggered apoptosis by inducing depolarization of mitochondrial potential and release of cytochrome c, downregulation of Mcl-1 and XIAP. Furthermore, triptolide significantly abrogated the growth of imatinib-resistant HMC-1.2 cell xenografts in nude mice and decreased KIT expression in xenografts. Our data demonstrate that triptolide inhibits imatinib-resistant mast cells harboring D816V KIT. Further investigation of triptolide for treatment of human neoplasms driven by gain-of-function KIT mutations is warranted.
Insights
Triptolide effectively inhibits mast cell growth, including imatinib-resistant D816V KIT mutations, by targeting KIT signaling pathways. This natural compound shows promise for treating KIT-driven cancers like systemic mastocytosis.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gain-of-function mutations in the receptor tyrosine kinase KIT drive systemic mastocytosis and GIST.
- Imatinib effectively treats many KIT-mutant cancers, but resistance, particularly the D816V mutation, remains a challenge.
Purpose of the Study:
- To investigate the efficacy of triptolide, a natural compound, against KIT-driven cellular models, including those with imatinib-resistant D816V KIT mutations.
- To elucidate the molecular mechanisms underlying triptolide's anti-cancer activity.
Main Methods:
- Triptolide treatment of human (HMC-1.1, HMC-1.2) and murine (P815) mast cell lines with varying KIT mutations.
- Analysis of cell growth, apoptosis, KIT mRNA levels, and downstream signaling pathways (Stat3, Akt, Erk1/2).
- In vivo evaluation using a nude mouse xenograft model with imatinib-resistant HMC-1.2 cells.
Main Results:
- Triptolide potently inhibited the growth of mast cells with both imatinib-sensitive and D816V KIT mutations.
- Triptolide reduced KIT mRNA and downstream signaling proteins (p-Stat3, p-Akt, p-Erk1/2), inducing apoptosis via mitochondrial pathways.
- Triptolide significantly suppressed tumor growth in vivo and reduced KIT expression in xenografts.
Conclusions:
- Triptolide demonstrates significant anti-proliferative and pro-apoptotic effects on KIT-mutant mast cells, including imatinib-resistant D816V variants.
- Triptolide targets KIT signaling and downstream effectors, offering a potential therapeutic strategy for KIT-driven neoplasms.
- Further research into triptolide for treating human cancers with gain-of-function KIT mutations is warranted.
