Antitumor activity of sorafenib in FLT3-driven leukemic cells

Abstract

Activating internal tandem duplication (ITD) insertions in the juxtamembrane domain of the FLT3 tyrosine kinase are found in about one fourth of patients with acute myeloid leukemia and have been shown to be an independent negative prognostic factor for survival. We show that sorafenib (BAY 43-9006, Nexavar) potently inhibits FLT3 enzymatic and signaling activities. In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, sorafenib blocked basal and ligand dependent FLT3-mediated tyrosine autophosphorylation as well as extracellular signal-regulated kinase1/2 and Stat5 phosphorylation. In leukemia cell lines MV4-11 and EOL-1, sorafenib treatment resulted in decreased cell proliferation and inhibition of FLT3 signaling. The growth of the FLT3-independent RS4-11 cell line was only weakly inhibited by sorafenib. Cell cycle arrest and induction of apoptosis were observed upon treatment with sorafenib in MV4-11 and EOL-1 cells. The antitumor efficacy of sorafenib was evaluated against the MV4-11 leukemia grown subcutaneously in NCr nu/nu mice. Doses of 3 and 10 mg/kg administered orally for 14 days resulted in six and nine out of 10 animals with complete responses, respectively. The demonstration that sorafenib exhibits potent target inhibition and efficacy in FLT3-driven models suggests that this compound may have a therapeutic benefit for patients with FLT3-driven leukemias.

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

“…For tumor cell lines with a single activating oncogenic tyrosine kinase mutation [such as MV4-11 and EOL-1 leukemic cell lines that contain a Flt-3 gene, mutant T670I cKIT that renders patients with gastrointestinal stromal tumor refractory to imatinib (29,30), or oncogenic RET variants (15,31) in metastatic thyroid cancer; ref. 32], the antiproliferative activity of sorafenib is in the low nanomolar concentration range (14,33). For tumor cell lines without an activating receptor tyrosine kinase mutation and with multiple signaling pathways driving cell growth, the antiproliferative activity of sorafenib is in the low micromolar concentration range.…”

Nilotinib Induces Autophagy in Hepatocellular Carcinoma through AMPK Activation

“…Advanced or recurrent HCC is frequently resistant to conventional chemotherapeutic agents and radiation, and thus remains one of the most difficult cancers to treat (2). Sorafenib, a multi-targeted receptor tyrosine kinase (RTK) inhibitor that targets the Raf kinases and other kinases such as VEGFR1-3, PDGFR-␤, FLT-3, and c-kit (1,(3)(4) has shown survival benefits in patients with advanced HCC and was approved for use in HCC by the United States Food and Drug Administration in 2007 (5-7). However, sorafenib only provides a modest effect, prolonging survival in patients with HCC from a median 7.9 to 10.7 months.…”

Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia

“…Inhibition of MV4-11 proliferation was chosen as the first cellular assay. This cell line has been used extensively when characterizing FLT3 enzyme A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 19 inhibitors both in cell-kill assays and in xenografts [25,38,39]. Compounds with an IC 50 below 400 nM in the MV4-11 cell line were then tested in another cellular assay, using the rapidly A c c e p t e d M a n u s c r i p t …”