Activation of LYN Kinase Linked to Imatinib Resistance in CML.

Tag : resistance

Activation of the LYN kinase enzyme is associated with resistanceto imatinib in patients with chronic myelogenous leukemia (CML),according to a study in the Journal of the National Cancer Institute (2008;100:927-940) .
Although some CML patients develop resistance in response tomutations in the BCR-ABL gene, in other cases, there have been noapparent mutations to explain the resistance. A news release notesthat previous work by Nicholas Donato, PhD, of the University ofMichigan Comprehensive Cancer Center and others suggested that onepossible mechanism of this mutation-negative resistance is theactivation of LYN kinase, which is normally controlled by BCR-ABLin CML cells.
In the new study, Dr. Donato and colleagues expanded on that workand examined the impact of overexpression and gene silencing of LYNkinase in CML cell lines treated with imatinib. They alsodetermined the level of LYN activation in samples from 12imatinib-resistant patients who lacked BCR-ABL mutations and sixwhose tumor cells were sensitive to the drug but who were unable totolerate its side effects.
Overexpression and activation of LYN kinase was associated withimatinib resistance in both cell lines and patient samples.Moreover, when these cells were treated with imatinib, BCR-ABLactivity was suppressed as happens in CML cells sensitive to thedrug, but LYN activation was not suppressed. When the researchersblocked expression of the LYN gene in the resistant cells, theyrestored imatinib responsiveness and triggered cell death.
These studies expand the spectrum of cellular changes that occurduring imatinib therapy beyond outgrowth of cells with BCR-ABLpoint mutations and support the use of other tyrosine kinaseinhibitors to treat a broad spectrum of imatinib-resistant CMLpatients, Dr. Donato and his coauthors wrote.
In an accompanying editorial, Michael Deininger, MD, PhD, of OregonHealth and Science University Cancer Institute and his colleaguesThomas O'Hare, PhD, and Christopher A. Eide, MD, note that the useof primary patient samples in the current study is particularlyimportant and provides clues as to how consistent LYN activationmay occur in CML. Further elucidation of this pathway will beessential, as will surveying a larger patient sample to determinehow frequently this type of resistance develops in CML patients.
The work takes us outside of the realm of thoroughly studied kinasedomain mutation-based resistance and toward an improvedunderstanding of BCR-ABL-independent disease, the editorialconcludes. In addition to opening new questions for exploration,these results suggest that therapies targeting both BCR-ABL and LYNkinases may prove beneficial in certain circumstances ofimatinib-resistant CML.