Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970

Abstract

IntroductionKIT is a receptor tyrosine kinase (RTK) of the type III subgroup, characterized by 5 extracellular immunoglobulin-like domains and a split tyrosine kinase domain. 1 Stem cell factor (SCF) binding induces dimerization and transphosphorylation, activating multiple signaling pathways, including mitogen-activated protein (MAP) kinases, Src kinases, Janus kinases/signal transducers and activators of transcription (Jaks/Stats), and phosphatidylinositol-3 (PI3) kinase. 1 Oncogenic mutations of KIT occur in diverse malignancies including gastrointestinal stromal tumors (GISTs), sinonasal natural killer (NK)/T-cell lymphoma, seminomas/dysgerminomas, acute myelogenous leukemia (AML), and systemic mastocytosis (SM). [2][3][4] The site of mutation tends to be cell-type specific. For example, 57% to 70% of GISTs have activating point mutations or small deletions in the juxtamembrane region of KIT. 3 In contrast, nearly all patients with SM exhibit a mutation in codon 816, typically an aspartate to valine substitution (D816V). 2,3,5 The D816V mutation, within the activation loop of the kinase, produces ligandindependent activation, increases the catalytic activity of KIT, and alters substrate specificity leading to aberrant signaling. [6][7][8] Codon 816 mutations were also reported in AML, as were small deletions in exon 8 in the extracellular region of KIT, typically concurrent with core binding factor mutations. [9][10][11] Treatment of SM is primarily symptomatic, although cladribine and interferon-␣ have some effect. 12,13 AML with core binding factor mutations generally carries a good prognosis, but KIT mutations in this group confer a higher risk of relapse. 9 Therefore, specifically targeting D816 mutant KIT may improve treatment of these malignancies.Various small molecule inhibitors of KIT have been developed, including FLT3 tyrosine kinase inhibitors [14][15][16] and imatinib mesylate, initially designed to target Bcr-Abl. 17 The sensitivity of KIT mutants to small molecule inhibitors depends on the nature of the mutation. Imatinib, for example, potently inhibits KIT juxtamembrane mutants and induced partial responses in 54% of GIST patients in phase 2 clinical trials. 3,18 In contrast, imatinib does not target D816 mutant KIT and is therefore ineffective in mastocytosis patients harboring these mutations. [19][20][21][22] In this study we assess the inhibitory potency of the tyrosine kinase inhibitors MLN518 (formerly CT53518) 14 and PD180970 23,24 against 2 classes of KIT mutations to determine whether these compounds might be useful for treatment of SM and other KIT-driven malignancies. Study design Cell linesThe Ba/F3 mouse pro-B-cell line and P815, a mouse mastocytoma cell line expressing murine D814Y KIT, were purchased from American Type Culture Collection (ATCC; Manassas, VA). The HMC-1 human mast cell line containing an activating juxtamembrane domain point mutation (V560G) 25 and One of the authors (C.L.R.) has declared a financial interest in a company (Millennium Pharmaceuticals) whose produ...

Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target

“…[15][16][17]20). The proliferation The inhibitory effect of imatinib is essentially restricted to the GIST cells that express only the wild-type kinase.…”

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

“…BIRB-796 is a p38 inhibitor that has been in clinical trials for inflammatory disease (23). MLN-518 and SU-11248 are inhibitors of wild-type and activated KIT and FLT3 (33)(34)(35)(36), and both have been in clinical trials for treatment of acute myeloid leukemia (25, 37) (Pharmaprojects database). SU-11248 is also in late-stage clinical trials for treatment of imatinib-resistant GIST.…”

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

“…[9][10][11][12][13][14][15] Dasatinib (BMS-354825) is a novel, potent, oral, multitargeted kinase inhibitor that targets ABL, SRC, KIT, PDGFR, and other tyrosine kinases. Dasatinib is structurally unrelated to imatinib 16 and is currently showing great promise for the treatment of all stages of imatinib-resistant and -intolerant chronic myeloid leukemia (CML) in early clinical development.…”