Therapeutic targeting of Src-kinase Lyn in myeloid leukemic cell growth

Abstract

Protein tyrosine kinases play a major role in promoting cell growth, and their activity in solid tumors is well established. Inhibitors of protein tyrosine kinases are now in advanced clinical trials for the treatment of breast and brain cancers. Because Src-related PTK have been shown to be activated in leukemic cell lines, we studied their activation in human myeloid leuke-mia. Blasts from the majority of patients with acute leukemia showed constitutive activity of the Src kinase Lyn. In contrast, no patient samples showed constitutive activation of Jak2. Genetic and pharmacologic targeting of Lyn was used to determine its contribution to leukemic cell growth. Antisense Lyn oligonucleotide treatment resulted in the inhibition of tritiated thymidine incorporation following GM-CSF stimulation of the factor-dependent line MO7e. The Src kinase inhibitor PD166285 inhibited the growth of human leukemic cell lines and leukemic blasts. When combined with doxorubicin, an additive effect on the inhibition of leukemic cell growth occurred. These studies demonstrate the importance of Src kinases in promoting leu-kemic cell growth and suggests that further development of agents which target Src kinases and their inclusion in multi-drug regimens are warranted for novel therapies of myeloid leukemia.

Role of Src expression and activation in human cancer

“…Reduced expression of any of these properties would potentially induce retarded tumor growth and reduction of metastatic tendencies. The recent use of Src inhibitors or antisense therapy in nude mouse studies , pancreatic cell growth , and leukemia cells (Roginskaya et al, 1999) supports the validity of this hypothesis. Numerous in vitro studies have been conducted to investigate the eects of Src speci®c inhibitors, general tyrosine kinase inhibitors, and growth factor receptor inhibitors.…”

“…Src family kinases Lck, Lyn, and Fgr have similarly been shown to be activated during leukemic cell growth (Abts et al, 1991) (Dai et al, 1998;Danhauser-Riedl et al, 1996;Roginskaya et al, 1999).…”

Activation of Stat3 preassembled with platelet-derived growth factor β receptors requires Src kinase activity

“…To directly test the requirement for Src in Stat3 activation by PDGF, density-arrested Balb/c-3T3 cells were pretreated with or without the Src kinase inhibitor, PD180970 (at 1 mM), and subsequently exposed to PDGF for 30 min in the presence or absence of inhibitor; whole-cell extracts were prepared and analysed for hSIE binding activity by EMSA. PD180970 is a member of a group of inhibitors that speci®cally inhibits the kinase activity of Src family members when used at appropriate concentrations (for PD180970, less that than 5 mM; Allgayer et al, 1999;Roginskaya et al, 1999;Kraker et al, submitted). As shown in Figure 6a, three hSIE binding activities, corresponding to Stat3/3, Stat1/3 and Stat1/1 complexes, were evident in cells receiving PDGF alone, and activation of all three was abolished by co-treatment of cells with PD180970.…”

Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors

“…14 Additionally, inhibitors of Src kinases have been shown to block blood cell function and leukemic cell growth. 31 Despite the fact that many SFKs are known to be present in MKs and platelets, no role for these kinases have previously been defined in MK development. 32,33 In this report, we provide convincing evidence that TPO stimulation results in activation of SFKs and that this signaling event reduces the proliferative response in cell lines and primary cells.…”