July 1, 2008

LYN Kinase Affects Sensitivity to Gleevec® in Chronic Myeloid Leukemia


LYN Kinase Affects Sensitivity to Gleevec® in Chronic Myeloid Leukemia

A protein structure known as the LYN kinase appears to play an important role in the effectiveness of Gleevec® (imatinib mesylate) in chronic myeloid leukemia (CML) cancer cells. These results were recently published in the Journal of the National Cancer Institute.

Chronic myeloid leukemia is a cancer that originates in the immune cells. It affects approximately 4,600 people annually in the United States. In the case of CML, large numbers of young immune cells do not mature, resulting in an excess accumulation of these cells. These leukemia cells then crowd the bone marrow and blood, suppressing formation and function of other blood cells normally present in these areas. In addition, the leukemia cells cannot perform their function properly, leaving patients susceptible to infection.

Chronic myeloid leukemia begins with a chronic phase, during which few or no clinical problems occur. However, when left untreated, the chronic phase progresses into acute phases; these phases, called the accelerated and blastic phases, are characterized by fast-growing and aggressive cancer. Patients reaching these acute phases have a poor prognosis for long-term survival.

Philadelphia chromosome-positive (Ph-positive) CML refers to the majority of cases of CML in which a genetic abnormality, referred to as the Philadelphia chromosome, results in the constantly activated growth of cancer cells. Roughly 30% of adult patients with acute lymphocytic leukemia (ALL) also have this genetic abnormality.

Gleevec is a biological agent that binds to and slows or stops the uncontrolled growth of cancer cells with the Philadelphia chromosome genetic mutation. Although Gleevec produces sustained anticancer responses in a significant portion of patients with Ph-positive CML, some patients never respond to Gleevec. ®Researchers have been exploring potential molecular markers or genetic mutations that may provide insight into why some patients do not respond to Gleevec while others experience significant and long-term responses.

Researchers from the University of Michigan recently conducted a clinical study to evaluate the potential role of the LYN kinase, a protein structure that is implicated in some aspects of cellular growth.® LYN kinase is thought to regulate survival and responsiveness in some CML cells. Laboratory studies have demonstrated that there are differences in LYN regulation between CML cells that respond to Gleevec and those that do not respond to Gleevec. The recent study included cancer cells from 12 patients with CML who did not respond to Gleevec and from six patients with CML who did respond to Gleevec but discontinued treatment because they could not tolerate the side effects of therapy. ®Within the trial agents such as Sprycel® (dasatinib) and effects of inhibition of LYN kinase were evaluated.

  • Treatment with Gleevec did not suppress action within the LYN kinase among cells from patients who did not respond to Gleevec.
  • Treating the cells with Sprycel resulted in cell death.
  • LYN kinase was independent of the effects of the Philadepha chromosome.

The researchers concluded that because the LYN kinase appears to affect resistance to Gleevec, it may provide insight to why some patients with Ph-positive CML do not respond to Gleevec. Further study is necessary to confirm these findings. Patients diagnosed with CML who do not respond to Gleevec may wish to speak with their physician regarding their individual risks and benefits of participation in a clinical trial further evaluating the LYN kinase or other individual markers. Two sources of information regarding ongoing clinical trials include the National Cancer Institute (www.cancer.gov) and www.eCancerTrials.com.

Reference: Wu J, Meng F, Kong L-Y, et al. Association Between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. Journal of the National Cancer Institute [early online publication]. June 2008. DOI: doi:10.1093/jnci/djn188.

Related News:® Advances in the Management of Chronic Myeloid Leukemia (01/21/2008)

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Tags: Chronic Myeloid Leukemia, Uncategorized