The antitumor activity of homoharringtonine against human mast cells harboring the KIT D816V mutation.
Gain-of-function mutations of the receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. The various juxtamembrane type of KIT mutations, including V560G, are found in 60% to 70% of patients with gastrointestinal stromal tumors; loop mutant D816V, which exists in approximately 80% of SM patients, is completely resistant to imatinib. In the present study, we hypothesized that homoharringtonine (HHT), a protein synthesis inhibitor, would decrease the level of KIT protein by inhibiting translation, resulting in a decreased level of phospho-KIT and abrogating its constitutive downstream signaling. 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 HHT and analyzed in terms of growth, apoptosis, and signal transduction. The in vivo antitumor activity was evaluated by using the murine mast cell leukemia model. Our results indicated that HHT effectively inhibited the growth and induced apoptosis in cells bearing both V560G and D816V or D814Y KIT. Additionally, HHT inhibited the KIT-dependent phosphorylation of downstream signaling molecules Akt, signal transducer and activator of transcription 3 and 5, and extracellular signal-regulated kinase 1/2. Furthermore, HHT significantly prolonged the survival duration of mice with aggressive SM or mast cell leukemia by inhibiting the expansion and infiltration of imatinib-resistant mast tumor cells harboring imatinib-resistant D814Y KIT. Collectively, we show that HHT circumvents D816V KIT-elicited imatinib resistance. Our findings warrant a clinical trial of HHT in patients with SM harboring D816V or D814Y KIT.
Jin
Yanli
Y
Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China.
Lu
Zhongzheng
Z
Cao
Kaiyuan
K
Zhu
Yunhui
Y
Chen
Qi
Q
Zhu
Feng
F
Qian
Chenchen
C
Pan
Jingxuan
J
D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D020868:Gene Silencing / Q000187:drug effects; D006248:Harringtonines / Q000494:pharmacology*; D000077863:Homoharringtonine; D006801:Humans; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D016019:Survival Analysis
D000970:Antineoplastic Agents; D006248:Harringtonines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D000077863:Homoharringtonine; D019009:Proto-Oncogene Proteins c-kit