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.