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Discovery Points to Factors in Imatinib Resistance

LYN kinase implicated in resistance in BCR-ABL mutation-negative chronic myelogenous leukemia

WEDNESDAY, June 25 (HealthDay News) -- LYN kinase may play a role in imatinib resistance in patients with chronic myelogenous leukemia who don't have BCR-ABL mutations, according to research published in the July 2 issue of the Journal of the National Cancer Institute.

Ji Wu, M.D., of the M.D. Anderson Cancer Center in Houston, and colleagues analyzed data from experiments using cells from patients with imatinib-resistant chronic myelogenous leukemia (CML) who didn't have BCR-ABL mutations -- previously thought to play a major role in imatinib resistance -- as well as cells from imatinib-sensitive patients and drug-resistant and drug-sensitive CML cell lines.

In imatinib-sensitive cells and cell lines, drug treatment suppressed LYN phosphorylation, but it didn't in cells from resistant patients without BCR-ABL mutations, the investigators found. In cells from resistant patients, imatinib did block BCR-ABL signaling, but failed to suppress LYN phosphorylation. The use of short interfering RNAs to silence LYN or tyrosine kinase inhibitors to reduce activation was associated with cytogenetic or complete hematological response in drug-resistant disease, the authors report.

"BCR-ABL-independent resistance is probably more frequent than generally appreciated and of considerable clinical importance," write Thomas O'Hare, Ph.D., and colleagues from the Oregon Health & Science University Cancer Institute in Portland, Ore., in an accompanying editorial. This study "takes us outside of the realm of thoroughly studied kinase domain mutation-based resistance and toward an improved understanding of BCR-ABL-independent disease. In addition to opening new questions for exploration, these results suggest that therapies targeting both BCR-ABL and LYN kinases may prove beneficial in certain circumstances of imatinib-resistant CML."

A study co-author disclosed relationships with Novartis and Bristol-Myers Squibb.

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