Abstract

Imatinib (IM) is a higherly effective targeted drug for CML. However, some CML patients, especially accelerated and blast crisis phase, often relapse due to drug resistance resulting from the emergence of IM-resistant point mutations within the BCR-ABL tyrosine kinase domain. This stimulates the development of new kinase inhibitors that are able to override resistance to IM. HHGV678 is a novel tyrosine kinase inhibitor and we employed IM-sensitive (K562 and 32Dp210) and resistant (K562R and fifteen 32Dp210 mutants) BCR-ABL+ cell lines to compare HHGV678 with IM on growth inhibition. In addition, synergistic effect of HHGV678 with IM was observed in 32Dp210 and 5 BCR-ABL mutants frequently observed in CML patients. MTT assay results showed that the estimated IC50 value of HHGV678 for K562 and 32Dp210 were 15.5 and 28-fold, for K562R and 15 BCR-ABL mutants, were 1.4–124.0-fold lower than that of IM, indicating that HHGV678 was a more effective than IM against cell growth of IM-sensitive and resistant cells. Using combination index analysis, HHGV678 displayed synergistic growth inhibition when used with IM in BCR-ABL mutants (M244V, Q252H, Y253H, E255K and T315I). HHGV678, combined with IM at their IC50 concentration induced apoptosis 2–5 fold higher than that of HHGV678 alone in BCR-ABL mutants respectively, by annexin-V staining. At the same condition, HHGV6787 resulted in remarkable decrease in CrKL phosphorylation as determined by western blot. We conclude that HHGV678 have significant activity against IM-sensitive and resistant BCR-ABL+ cell, especially when it combined with IM that warrant further investigation in clinical trials.

Disclosures: No relevant conflicts of interest to declare.

Author notes

Corresponding author