kw-2449 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Chronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with crucial pathogenic protein named BCR-ABL, which endangers the life of patients severely. As a milestone of targeted drug, Imatinib has achieved great success in the treatment of CML. Nevertheless, inevitable drug resistance of Imatinib has occurred frequently in clinical due to the several mutations in the BCR-ABL kinase. Subsequently, the second-generation of tyrosine kinase inhibitors (TKIs) against BCR-ABL was developed to address the mutants of Imatinib resistance, except T315I. To date, the third-generation of TKIs targeting T315I has been developed for improving the selectivity and safety. Notably, the first allosteric inhibitor has been in market which could overcome the mutations in ATP binding site effectively. Meanwhile, some advanced technology, such as proteolysis-targeting chimeras (PROTAC) based on different E3 ligand, are highly expected to overcome the drug resistance by selectively degrading the targeted proteins. In this review, we summarized the current research progress of inhibitors and degraders targeting BCR-ABL for the treatment of CML.

Topics: Antineoplastic Agents; Benzamides; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Protein Kinase Inhibitors; Pyrimidines

The purpose of this study was to determine whether histone deacetylase (HDAC) inhibitors (HDACI) such as vorinostat or entinostat (SNDX-275) could increase the lethality of the dual Bcr/Abl-Aurora kinase inhibitor KW-2449 in various Bcr/Abl(+) human leukemia cells, including those resistant to imatinib mesylate (IM).. Bcr/Abl(+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) cells, including those resistant to IM (T315I, E255K), were exposed to KW-2449 in the presence or absence of vorinostat or SNDX-275, after which apoptosis and effects on signaling pathways were examined. In vivo studies combining HDACIs and KW2449 were carried out by using a systemic IM-resistant ALL xenograft model.. Coadministration of HDACIs synergistically increased KW-2449 lethality in vitro in multiple CML and Ph(+) ALL cell types including human IM resistant cells (e.g., BV-173/E255K and Adult/T315I). Combined treatment resulted in inactivation of Bcr/Abl and downstream targets (e.g., STAT5 and CRKL), as well as increased reactive oxygen species (ROS) generation and DNA damage (γH2A.X). The latter events and cell death were significantly attenuated by free radical scavengers (TBAP). Increased lethality was also observed in primary CD34(+) cells from patients with CML, but not in normal CD34(+) cells. Finally, minimally active vorinostat or SNDX275 doses markedly increased KW2449 antitumor effects and significantly prolonged the survival of murine xenografts bearing IM-resistant ALL cells (BV173/E255K).. HDACIs increase KW-2449 lethality in Bcr/Abl(+) cells in association with inhibition of Bcr/Abl, generation of ROS, and induction of DNA damage. This strategy preferentially targets primary Bcr/Abl(+) hematopoietic cells and exhibits enhanced in vivo activity. Combining KW-2449 with HDACIs warrants attention in IM-resistant Bcr/Abl(+) leukemias.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Fusion Proteins, bcr-abl; Histone Deacetylase Inhibitors; Humans; Imatinib Mesylate; Indazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Inbred BALB C; Mice, SCID; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Xenograft Model Antitumor Assays