CGP 57148, a Tyrosine Kinase Inhibitor, Inhibits the Growth of Cells Expressing BCR-ABL, TEL-ABL, and TEL-PDGFR Fusion Proteins

Abstract

CGP 57148 is a compound of the 2-phenylaminopyrimidine class that selectively inhibits the tyrosine kinase activity of the ABL and the platelet-derived growth factor receptor (PDGFR) protein tyrosine kinases. We previously showed that CGP 57148 selectively kills p210BCR-ABL–expressing cells. To extend these observations, we evaluated the ability of CGP 57148 to inhibit other activated ABL tyrosine kinases, including p185BCR-ABL and TEL-ABL. In cell-based assays of ABL tyrosine phosphorylation, inhibition of ABL kinase activity was observed at concentrations similar to that reported for p210BCR-ABL. Consistent with the in vitro profile of this compound, the growth of cells expressing activated ABL protein tyrosine kinases was inhibited in the absence of exogenous growth factor. Growth inhibition was also observed with a p185BCR-ABL–positive acute lymphocytic leukemia (ALL) cell line generated from a Philadelphia chromosome–positive ALL patient. As CGP 57148 inhibits the PDGFR kinase, we also showed that cells expressing an activated PDGFR tyrosine kinase, TEL-PDGFR, are sensitive to this compound. Thus, this compound may be useful for the treatment of a variety of BCR-ABL–positive leukemias and for treatment of the subset of chronic myelomonocytic leukemia patients with a TEL-PDGFR fusion protein.

H. pyloriselectively blocks EGFR endocytosis via the non-receptor kinase c-Abl and CagA

“…In contrast to STI treatment, c-Abl RNAi experiments did not appear to fully attenuate the response. This can be due to the fact that STI also blocks the activity of other kinases, like PDGFR and c-kit, indicating a possible minor involvement of kinases besides c-Abl (Carroll et al, 1997;Heinrich et al, 2000;Nurmio et al, 2008). Nevertheless, knockdown of c-Abl leads to a significant decrease of EGFR surface expression, supporting the notion that c-Abl inhibits EGFR endocytosis.…”

ERK signaling pathway is differentially involved in erythroid differentiation of K562 cells depending on time and the inducing agent

“…Inhibition of the BCReABL tyrosine kinase, its connection to Ras, Ras itself, or further signaling through Raf and MEK-1 lead to both growth inhibition and spontaneous erythroid differentiation in K562 cells (Anafi et al, 1993;Carroll et al, 1997;Druker et al, 1996;Fang et al, 2000;Gishizky et al, 1995;Honma et al, 1989;Kang et al, 1999;Shelly et al, 1998). Our results on the effect of MEK-1 inhibitors in K562 cells confirm previous studies demonstrating that inhibition of signaling through ERK inhibits growth and induces erythroid differentiation in K562 cells (Kang et al, 1999;Park et al, 2001;Witt et al, 2000).…”

“…The ERK kinase cascade is a wellrecognized key regulator of mammalian cell proliferation, differentiation and development, which is involved in erythroid differentiation in different model systems with conflicting results. Blocking signaling through the classical RaseRafeMEK-1eERK pathway in human K562 erythroleukemia cells inhibits proliferation and induces spontaneous erythroid differentiation (Anafi et al, 1993;Carroll et al, 1997;Druker et al, 1996;Fang et al, 2000;Gishizky et al, 1995;Honma et al, 1989;Kang et al, 1999). However, enhancing ERK activity by overexpressing Ras resulted in erythroid differentiation of K562 cells as well (Kang et al, 1999).…”

Combined inhibition of VEGF‐ and PDGF‐signaling enforces tumor vessel regression by interfering with pericyte‐mediated endothelial cell survival mechanisms

“…Furthermore, interference with PDGF-B/PDGFR-β signaling resulted in disruption of already established endothelial/pericyte associations and vessel destabilization during retinal development (19). Therefore, the use of inhibitors of the PDGFR-β tyrosine kinase should provide a novel means to interfere with pericyte function during tumor angiogenesis (20)(21)(22).…”