Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back.

Abstract

Cancer research within the last decades elucidated signaling pathways and identified genes and proteins that lead or contribute to malignant transformation of a cell. Discovery of the Bcr-Abl oncoprotein as the molecular abnormality causing chronic myeloid leukemia (CML) paved the way for the development of a targeted anticancer therapy. The substantial activity of imatinib mesylate (STI571, Glivec) in CML and Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) changed the therapeutic approach to Ph+ leukemia and rang the bell for a new era of anticancer treatment. However, when the phenomenon of relapse occurred despite continued imatinib treatment, we had to learn the lesson that imatinib can select for a resistant disease clone. If such a clone still depends on Bcr-Abl, it either carries a BCR-ABL point mutation that prevents binding of the drug or expresses the fusion protein at high levels. Alternatively, leukemia cells that harbor secondary genetic alterations resulting in Bcr-Abl-independent proliferation are selected for their growth advantage in the presence of imatinib. Point mutations in the BCR-ABL kinase domain prevent binding of imatinib but still allow binding of ATP, thus retaining Bcr-Abl kinase activity. Mutated BCR-ABL is frequently detected in cases of imatinib-resistant Ph+ leukemia and therefore represents the main challenge for the investigation of alternative strategies to either overcome resistance or to prevent the emergence of a resistant leukemic clone.

• Authors: N von Bubnoff, C Peschel, J Duyster
• Journal: Leukemia (Leukemia) Vol. 17 Issue 5 Pg. 829-38 (May 2003) ISSN: 0887-6924 [Print] England
• PMID: 12750693 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl

Topics

• Antineoplastic Agents (therapeutic use)
• Benzamides
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics)
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Piperazines (therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (therapeutic use)