Ever since the approval of Gleevec in 2001, a cancer-cell-specific drug used to treat chronic myelogenous leukemia (CML), the field of cancer therapeutics has been rushing full speed into the era of so-called "targeted" medicines. The challenge of developing these medicines, which spare normal cells because they are designed to kill only cancer cells, has been complicated by the recognition that resistance to even targeted therapies can develop. In the case of Gleevec, for example, which disables the BCR-ABL1 protein that causes CML, resistance has become a growing problem. Currently, physicians estimate that 5 percent to 10 percent of patients who begin treatment in the chronic phase of their disease will develop resistance to Gleevec; and if treatment is begun at more advanced stages of CML, this percentage is much higher.
Now researchers at the Abramson Cancer Center of the University of Pennsylvania have found a way around this problem. By disabling a BCR-ABL1-associated enzyme called Lyn kinase, they have induced cell death in drug-resistant CML cells taken from CML patients. Normal blood cells do not appear to be harmed by this approach because they are not so dependent on the Lyn kinase as CML cells. The Lyn kinase is therefore a good candidate for a targeted therapy. "We know that patients treated with Gleevec can develop mutations in the BCR-ABL1 protein," explains Alan M. Gewirtz, MD, Professor of Medicine in Penn’s Division of Hematology/Oncology. "Once the BCR-ABL1 gene mutates, Gleevec can no longer combine with the BCR-ABL1 protein, so it remains active, and the cancerous blood cells survive and grow." Gewirtz and colleagues’ research appears in the November issue of Nature Medicine.
"Lyn kinase is a member of a family of proteins that we know plays a role in cell survival, growth, and development," explains Gewirtz. "CML cells, especially those that arise in Gleevec-resistant patients, are very dependent on its function." To disable it, the researchers used short interfering RNA (siRNA) to "silence" the gene that codes for the Lyn kinase protein.
Karen Kreeger | EurekAlert!
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