Small Interfering RNA against Bcr-Abl Transcripts Sensitized Mutated T315I Cells to Nilotinib.

Selective inhibition of the BCR-ABL tyrosine kinase by RNA interference has been demonstrated in leukemic cells. Therefore, we evaluated the specific bcr-abl small interfering RNA (siRNA) silencing in BCR-ABL positive cell lines, including those resistant to imatinib (IM) and particularly those with the T315I mutation.

The factor-independent 32Dp210 bcr-abl oligoclonal cell lines and in human IM-resistant bcr-abl positive cells from different patients with leukemia disorders were investigated. The effects of bcr-abl siRNA or the combination of bcr-abl siRNA with both IM and nilotinib were compared with those of the ABL inhibitors IM and nilotinib.

Coadministration of bcr-abl siRNA with IM or nilotinib dramatically reduced the .{/MAIN;133}BCR-ABL expression in wild-type (wt) and mutated bcr-abl cells and increased the lethal capacity. The bcr-abl siRNA significantly induced apoptosis and inhibited proliferation in wt (p<0.0001) and mutated cells (H396P, T315I, p<0.0001) versus controls. Cotreatment of bcr-abl siRNA with IM or nilotinib resulted in an increased inhibition of proliferation and induction of apoptosis as compared to IM or nilotinib (p<0.0001) in T315I cells. Furthermore, the combination of bcr-abl siRNA with IM or nilotinib significantly (p<0.01) reversed multidrug resistance gene 1-dependent resistance of mutated cells. In T315I cells bcr-abl siRNA with nilotinib has shown powerful effect on the cell-cycle distribution.

Our data suggest that silencing by bcr-abl siRNA with IM or nilotinib may be associated with an additive antileukemic activity against tyrosine kinase inhibitor-sensitive and –resistant BCR-ABL cells, and might be an alternative approaches to overcome BCR-ABL mutations.

No relevant conflicts of interest to declare.