Abstract B57: Overcoming Acquired Resistance in Philadelphia-Positive (Ph+) Leukemia

Abstract

Abstract Chronic myeloid leukemia (CML) is characterized by the presence of p210Bcr-Abl which exhibits an abnormal kinase activity. Selective Abl kinase inhibitors (AKIs) have been successfully established for the treatment of CML. Despite high rates of clinical response, CML patients can develop resistance. Acquired resistance to AKIs in Ph+ leukemia is mostly due to the acquisition of point mutations within the Bcr-Abl Kinase by either reducing the affinity of the kinase domain to the ATP-competitor or stabilizing the active confirmation of the Abl kinase domain. Thus, acquired drug resistance in Philadelphia positive (Ph+) leukemia and in particular the gatekeeper mutation, T315I, to Abl kinase inhibitors (AKIs), represents a major obstacle in overcoming Bcr-Abl positive leukemia. T315I mutation is refractory to clinically available AKIs, as well as to Abl allosteric inhibitors such as GNF-2. In this study, we documented cooperation between AKIs and GNF-2 in inhibiting proliferation and clonigenicity of Ba/F3 cells carrying T315I mutated Bcr-Abl. Interestingly, cooperation was most evident between dasatinib and GNF-2. Cooperation was also documented in the ALL SupB15 cell line. Cooperation in cells carrying native Bcr-Abl gene was mediated by Bcr-Abl. In contrast, proliferation and clonigenicity inhibition of Ph+ cells harboring the T315I mutation was not mediated by Bcr-Abl, but apparently by Bcr-Abl-independent mechanisms. Moreover, previously we have identified oleic acid as the active component in the mushroom Daedalea gibbosa who inhibited the kinase activity of Bcr-Abl apparently by allosteric inhibition. Here, we report that derivatives of oleic acid, oleylamine-carbonyl L-valinol and oleylamine-carbonyl D-valinol, inhibited the activity of the native and T315I mutated Bcr-Abl. Furthermore, oleylamine-carbonyl L-valinol and oleylamine-carbonyl D-valinol, exhibited higher activity toward the oncogenic Bcr-Abl in comparison to native c-Abl in SupB15, Ph-positive ALL cell line.