Comparison of the Effects of Two Kinase Inhibitors, Sorafenib and Dasatinib, on Chronic Lymphocytic Leukemia Cells

Abstract

Background: With sorafenib displaying the highest affinities for Flt3, VEGFR (vascular endothelial growth factor receptor) and Raf and dasatinib for Abl and Src kinases, the profiles of kinases targeted by these inhibitors differ strongly. Materials and Methods: Dose-dependent effects of the inhibitors on freshly isolated chronic lymphocytic leukemia (CLL) cells were assessed as increased phosphatidylserine exposure. Inhibition by sorafenib and dasatinib of survival and anti-apoptotic signaling in CLL cells was examined by Western blot analysis. Results: Sorafenib uniformly induced apoptosis in CLL lymphocytes with a concentration inhibiting by 50% (IC50) of 8 mM, whereas the response to dasatinib was heterogeneous with the onset of inhibition at submicromolar concentrations but with IC50 values below 25 mM in only a few samples. At the respective pharmacologically achievable plasma concentrations, the inhibitors showed more efficient apoptosis induction by sorafenib than by dasatinib and less than additive mutual enhancement in combination. Co-culture with the bone marrow stroma cell line HS-5 increased the viability of untreated CLL cells but did not protect from sorafenib-induced apoptosis. Conclusions: Sorafenib or dasatinib displayed sigmoidal or saturation-type dose-response relationships for apoptosis induction, which were uniform or highly divergent, respectively, among individual CLL samples and therefore might complement each other in their clinical potential for CLL.

Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia

“…Sorafenib, a multikinase inhibitor targeting Raf-kinases and several proangiogenic RTKs, 39 induces rapid cell death in primary CLL cells, even in the presence of stromal cells. 15,16,[21][22][23] In full agreement with these studies, 10 mM sorafenib, a concentration comparable with the plasma levels of this drug in patients, 21,40 killed more than 50% of freshly isolated CLL cells, whereas the more specific B-Raf (PLX4720) and MEK (U0126) inhibitors had no significant effects on viability ( Figure 5B). We attribute the failure of the B-Raf and MEK inhibitor to its well-described paradoxical MEK/ERK activation in cells lacking BRAF mutations 41 and the narrow target spectrum of U0126, respectively.…”

“…This finding is of particular interest, first because sorafenib is well characterized in clinical application and second because sorafenib potently induces apoptosis in primary CLL cells corresponding to distinct karyotypic subsets, even in the presence of the protective microenvironment. 15,16,[21][22][23] However, the target kinases of sorafenib responsible for this proapoptotic effect remain ill-defined for CLL. Recent publications concerning sorafenib treatment in CLL summarized that sorafenib exerts its effects via the inhibition of Raf and VEGFR, because CLL cells are not sensitive to the inhibition of KIT, PDGFR, and FLT3, but they remain sensitive to the inhibition of RAF and VEGFR.…”

“…Recent studies have shown that CLL cells might also be susceptible to this compound. 15,16,[21][22][23] However, little is known about its precise mode of action in CLL cells, in particular which signaling pathways affected by sorafenib might account for the observed cell death. The aim of the present study was to investigate the functional significance of IGF1R expression on CLL cells and to evaluate IGF1R as a potential target of sorafenib.…”

Efficacy of phosphatidylinositol‐3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells

“…Similarly, while 1 µM copanlisib inhibited the survival of CLL cells by more than 50% in the vast majority of samples, buparlisib exhibited IC 50 concentrations below the clinically obtainable plasma concentration of 5 µM only in one third of examined samples . Also taking into account the tolerated plasma concentrations, the cytotoxic potency of copanlisib for CLL cells exceeded that of idelalisib, duvelisib and buparlisib or other kinase inhibitors, e.g., dasatinib and sorafenib …”

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

“…No significant relationship between exposure and antitumor activity has been established for sorafenib to date. 48,114 A C trough target of 3750-4300 ng/mL, 115 also supported by preclinical studies, 116 has been suggested to be efficacious. However, because of lack of evidence for a target or range, dose adaptations based on this target cannot be recommended yet.…”