Synergistic interactions between imatinib and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib resistance.

Resistance to the Abl kinase inhibitor imatinib has become a critical issue for patients in advanced phases of chronic myelogenous leukemia. Imatinib-resistant tumor cells develop, in part, as a result of point mutations within the Abl kinase domain. As Akt plays a pivotal role in Abl oncogene-mediated cell survival, we hypothesize that concurrent inhibition of Akt will sensitize resistant cells to the residual apoptotic activity of imatinib, thereby overcoming the resistance. Here, we examined the effect of OSU-03012, a celecoxib-derived phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on imatinib-induced apoptosis in two clinically relevant Bcr-Abl mutant cell lines, Ba/F3p210(E255K) and Ba/F3p210(T315I). The IC50 values of imatinib to inhibit the proliferation of Ba/F3p210(E255K) and Ba/F3p210(T315I) were 14 +/- 4 and 30 +/- 2 microM, respectively. There was no cross-resistance to OSU-03012 in these mutant cells with IC50 of 5 microM irrespective of mutations. Nevertheless, in the presence of OSU-03012, the susceptibility of these mutant cells to imatinib-induced apoptosis was significantly enhanced. This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together, these data provide a novel therapeutic strategy to overcome imatinib resistance, especially with the Abl mutant T315I.