In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells

Abstract

Resistance to imatinib represents an important scientific and clinical issue in chronic myelogenous leukemia. In the present study, the effects of the novel inhibitor SKI-606 on various models of resistance to imatinib were studied. SKI-606 proved to be an active inhibitor of Bcr-Abl in several chronic myelogenous leukemia cell lines and transfectants, with IC 50 values in the low nanomolar range, 1 to 2 logs lower than those obtained with imatinib. Cells expressing activated forms of KIT or platelet-derived growth factor receptor (PDGFR), two additional targets of imatinib, were unaffected by SKI-606, whereas activity was found against PIM2. SKI-606 retained activity in cells where resistance to imatinib was caused by BCR-ABL gene amplification and in three of four Bcr-Abl point mutants tested. In vivo experiments confirmed SKI-606 activity in models where resistance was not caused by mutations as well as in cells carrying the Y253F, E255K, and D276G mutations. Modeling considerations attribute the superior activity of SKI-606 to its ability to bind a conformation of Bcr-Abl different from imatinib. (Cancer Res 2006; 66(23): 11314-22)

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

“…[81][82][83] Bosutinib is more active than imatinib in vitro and has minimal activity against PDGFR or c-kit. 84,85 In preliminary data from the phase 2 portion of a phase 1/2 study investigating bosutinib in patients with CML-CP and resistance or intolerance to imatinib, 75 of 96 evaluable patients (78%) achieved a CHR, 47 of 106 (44%) achieved an MCyR, and 35 (33%) achieved a CCyR. 86 An MMR was achieved in 27 of 85 patients (32%), of which 15 (18%) were complete molecular response (CMR).…”

Chronic myeloid leukemia: Second‐line drugs of choice

“…In such a circumstance two possibilities can be raised: that the residual Ph negative hematopoiesis of the patient is insufficient or that the inhibition of kinases important for the normal hemopoiesis, such as Kit, is relevant. In the latter case it is important to note that bosutinib is the only TKI known not to inhibit Kit [39]. Therefore bosutinib could be preferred in those patients in which residual hematologic toxicity persists after obtaining a cytogenetic response or in whom other causes for impaired hemopoiesis are present, such as a thalassemic trait or cyclic thrombocytopenia.…”

“…Bosutinib is a TKI that inhibits both BCR-ABL1 and SRC kinases, but is only minimally active against KIT and PDGFR [39], which is thought to contribute to its unique therapeutic and safety profile [29,30,67,68]. Bosutinib is currently licensed for the treatment of chronic, accelerated, or blast phase Ph1 CML in patients who are resistant or intolerant to prior therapy based on findings from a single-arm, phase I/II trial that included separate disease-phase cohorts [69].…”

Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors

“…Bosutinib (SKI-606) inhibits both BCR-ABL and Src, being 10-to 20-fold more potent against BCR-ABL than imatinib in vitro, but has no activity against the T315I mutation [87,88]. From preliminary data from a study in imatinib-resistant patients with CP CML, CCyRs were achieved by 30% of patients [89].…”