Abstract
The potency of Abelson (ABL) tyrosine kinase inhibitors (TKIs) against chronic myeloid leukemia (CML) has been demonstrated. However, ABL TKI resistance can develop. In this study, we investigated the efficacy of a combination therapy including rigosertib (ON 01910.Na), a polo-like kinase (PLK) and phosphoinositide 3-kinase (PI3K) inhibitor, and ABL TKIs. A 72-h rigosertib treatment was found to inhibit cell growth, induce apoptosis, reduce phosphorylation of the breakpoint cluster region-c (BCR)-ABL and its substrate Crk-L, and increase the activities of caspase 3 and poly (ADP-ribose) polymerase (PARP). This combination therapy also exerted a synergistic inhibitory effect on Philadelphia chromosome (Ph)-positive cell proliferation and reduced the phosphorylation of BCR-ABL and Crk-L while increasing that of cleaved PARP and the H2A.X histone. Rigosertib also potently inhibited the growth of ABL TKI-resistant cells, and cotreatment with ABL TKIs and rigosertib induced higher cytotoxicity. These results indicate that rigosertib treatment may be a powerful strategy against ABL TKI-resistant cells and could enhance the cytotoxic effects of ABL TKIs.
Highlights
Chronic myeloid leukemia (CML) is associated with the Philadelphia chromosome (Ph), which is a translocation of the Abelson (ABL)1 oncogene on chromosome 9 with a breakpoint cluster region (BCR) on chromosome 22 and is designated t(9;22) [1]
As rigosertib is a potent PLK1 and phosphoinositide 3-kinase (PI3K) inhibitor, we examined its efficacy against Ph-positive leukemia cells
We demonstrated that PLK1 protein was abundantly expressed in Ph-positive leukemia and CD34-positive primary CML cells
Summary
Chronic myeloid leukemia (CML) is associated with the Philadelphia chromosome (Ph), which is a translocation of the Abelson (ABL) oncogene on chromosome 9 with a breakpoint cluster region (BCR) on chromosome 22 and is designated t(9;22) [1]. This fusion gene encodes the chimeric oncogenic fusion protein BCRABL, a constitutively active tyrosine kinase. Second-generation ABL TKIs such as nilotinib or dasatinib have been shown to induce major cytogenetic responses in approximately 50% of patients with imatinib-resistant or intolerant CML [4, 5] and are currently used clinically as first-line therapies for newly diagnosed CML [6, 7]
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