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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 5)

Targeting BCR-ABL with Imatinib: Proof of Principle The protein product of the Philadelphia chromosome occurs in all patients with chronic myeloid leukemia (CML) and in ~30% of patients with adult acute lymphoid leukemia (ALL) and encodes the fusion protein Bcr-Abl. Although the c-Abl protooncogene is a nuclear protein whose kinase activity is tightly regulated as a part of the DNA damage response pathway (and actually induces growth arrest), the Bcr-Abl fusion protein is largely cytoplasmic with a constitutively activated tyrosine kinase domain. The deregulated tyrosine kinase activity of BcrAbl is required for its transforming activity. The Abl tyrosine kinase. | Chapter 080. Cancer Cell Biology and Angiogenesis Part 5 Targeting BCR-ABL with Imatinib Proof of Principle The protein product of the Philadelphia chromosome occurs in all patients with chronic myeloid leukemia CML and in 30 of patients with adult acute lymphoid leukemia ALL and encodes the fusion protein Bcr-Abl. Although the c-Abl protooncogene is a nuclear protein whose kinase activity is tightly regulated as a part of the DNA damage response pathway and actually induces growth arrest the Bcr-Abl fusion protein is largely cytoplasmic with a constitutively activated tyrosine kinase domain. The deregulated tyrosine kinase activity of Bcr-Abl is required for its transforming activity. The Abl tyrosine kinase inhibitor imatinib mesylate Gleevec has validated the concept of a molecularly targeted approach to cancer treatment. Imatinib is a low-molecular-weight competitive inhibitor of the ATP binding site of Bcr-Abl c-Abl platelet-derived growth factor receptor PDGFR and c-Kit hence it is not absolutely specific for the Bcr-Abl oncogene product Table 80-2 . Clinical studies have demonstrated remarkable activity of this agent in CML. In phase II studies of 532 chronic phase CML patients in whom interferon treatment had failed 95 obtained a hematologic complete response with only 9 relapse after a median follow-up of 18 months. With longer followup 75 of patients treated with imatinib in chronic phase remain in remission after nearly 4 years. Imatinib was also active in CML blast crisis with a 52 response rate although the responses were short-lived 78 relapse within 1 year . Relapse during treatment with imatinib was associated with reactivation of the tyrosine kinase either by amplification of the Bcr-Abl locus leading to increased levels of Bcr-Abl protein or more commonly by point mutations within the Bcr-Abl kinase domain that decreased imatinib binding without loss of Bcr-Abl kinase activity. These data constitute genetic proof that the target of imatinib is the