Researchers at Virginia Commonwealth University’s Massey Cancer Center have documented a novel form of resistance in leukemia cells to an anti-cancer drug, which could help scientists develop new strategies for treating the disease.
The drug, imatinib mesylate, is associated with the activation of an enzyme that is less susceptible to the action of the drug, according to Steven Grant, M.D., oncology professor and lead author of the study.
Research showed that the activation of the enzyme Lyn increases the expression of Bcl-2, a protein that opposes cell death in chronic myelogenous leukemia, or CML, cells. Once this pathway is activated, Lyn causes the leukemia cells to become resistant to chemotherapeutic drugs, including imatinib mesylate, according to the article published in the Aug. 13, 2004, issue of the Journal of Biological Chemistry.
CML is a cancer of the bone marrow caused by a specific genetic abnormality and is one of the most common forms of leukemia.
Imatinib mesylate previously has been highly effective in the treatment of CML because it inhibits Bcr/Abl, the primary gene responsible for the leukemia. However, once the Bcr/Abl gene has been inhibited by the drug, in some cases, Lyn becomes activated, thereby altering the regulation of Bcl-2, which causes the leukemia cells to become resistant to imatinib mesylate and other drugs.
Researchers examined the molecular profile of human CML cells that had become resistant to imatinib mesylate in association with the loss of Bcr/Abl gene and activation of Lyn.
“We observed that some leukemia cells experience loss of the Bcr/Abl gene while at the same time exhibiting increased activity of another class of oncogenes, a phenomenon that presumably compensates for the loss of the effects of the Bcr/Abl gene,” Grant wrote.
The Src kinase family, which includes Lyn, is generally not as susceptible to imatinib mesylate as the Bcr/Abl gene. Lyn is able to promote the survival of CML cells by altering expression of Bcl-2, causing their sensitivity to the drug to become diminished, he said.