Transient Potent BCR-ABL Inhibition Is Sufficient to Commit Chronic Myeloid Leukemia Cells Irreversibly to Apoptosis

Abstract

The BCR-ABL inhibitor dasatinib achieves clinical remissions in chronic myeloid leukemia (CML) patients using a dosing schedule that achieves potent but transient BCR-ABL inhibition. In vitro, transient potent BCR-ABL inhibition with either dasatinib or imatinib is cytotoxic to CML cell lines, as is transient potent EGFR inhibition with erlotinib in a lung cancer cell line. Cytotoxicity correlates with the magnitude as well as the duration of kinase inhibition. Moreover, cytotoxicity with transient potent target inhibition is equivalent to prolonged target inhibition and in both cases is associated with BIM activation and rescued by BCL-2 overexpression. In CML patients receiving dasatinib once daily, response correlates with the magnitude of BCR-ABL kinase inhibition, thereby demonstrating the potential clinical utility of intermittent potent kinase inhibitor therapy.

The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair

“…Indeed, inhibition of PI3K-mediated signaling also enhances apoptosis sensitivity in GBM cells in an NHEJ-independent manner, as we have previously shown for agents that do not primarily cause DNA damage, that is, death receptor ligands such as TRAIL and anti-CD95 agonistic antibody (Opel et al, 2008). Intriguingly, in line with recent observations regarding the pharmacokinetics of inhibitor-induced cancer cell death (Shah et al, 2008), we also found that a brief, but potent inhibition of PI3K administered concurrently with a DNA-damaging drug is sufficient to commit GBM cells to apoptosis and to suppress clonogenic growth.…”

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

“…Bim, a proapoptotic Bcl-2 homology 3-only protein (36), is elevated after ablation of Bcr-Abl and epidermal growth factor receptor signaling (37)(38)(39). However, our data showed that the levels of Bim were unperturbed after HHT treatment (Figs.…”

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

“…The CrkL protein has been observed with a total of 28 PTMs identified in MS experiments (see www.phosphosite.org), however only phosphorylated tyrosine 207 (pTyr207) has been validated (using a range of methods including western blot, site-directed mutatgenesis and flow cytometry 30,[49][50][51][52][53][54] ). Tyrosine 207 phosphorylation has been shown to be the principle phosphorylation event related to BCR-ABL activity 30 .…”