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...
Nội dung trích xuất từ tài liệu:
Chapter 080. Cancer Cell Biology and Angiogenesis (Part 5) 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 patientswith chronic myeloid leukemia (CML) and in ~30% of patients with adult acutelymphoid leukemia (ALL) and encodes the fusion protein Bcr-Abl. Although thec-Abl protooncogene is a nuclear protein whose kinase activity is tightly regulatedas a part of the DNA damage response pathway (and actually induces growtharrest), the Bcr-Abl fusion protein is largely cytoplasmic with a constitutivelyactivated 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 targetedapproach to cancer treatment. Imatinib is a low-molecular-weight competitive inhibitor of the ATPbinding 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 agentin CML. In phase II studies of 532 chronic phase CML patients in whominterferon treatment had failed, 95% obtained a hematologic complete response,with only 9% relapse after a median follow-up of 18 months. With longer follow-up, 75% of patients treated with imatinib in chronic phase remain in remissionafter 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 1year). Relapse during treatment with imatinib was associated with reactivation ofthe tyrosine kinase either by amplification of the Bcr-Abl locus leading toincreased levels of Bcr-Abl protein or, more commonly, by point mutations withinthe Bcr-Abl kinase domain that decreased imatinib binding without loss of Bcr-Abl kinase activity. These data constitute genetic proof that the target of imatinibis the Bcr-Abl tyrosine kinase, and that Bcr-Abl kinase activity is still required byimatinib-resistant cells. Two drugs have been developed (dasatinib and nilotinib)that are potent inhibitors against most imatinib resistant mutants; these compoundshave demonstrated significant activity in patients with imatinib-resistant CML. Table 80-2 FDA-Approved Molecularly Targeted Agents for theTreatment of Cancer Drug Molecular Disease Mechanism of Target Action All-trans PML-RARα Acute Inhibitsretinoic acid oncogene promyelocytic transcriptional(ATRA) leukemia M3 repression by the AML; t(15;17) PML-RARα Imatinib Bcr-Abl, c- Chronic Blocks ATP(Gleevec) Abl, c-Kit, myelogenous binding to tyrosine PDGFR-α/β, leukemia; GIST kinase active site. Sunitinib c-Kit, GIST; Inhibits(Sutent) VEGFR-2, renal cell cancer activated c-Kit and PDGFR-β, Flt-3 PDGFR in GIST; inhibits VEGFR in RCC. Sorafinib RAF, RCC; Targets VEGFR(Nexavar) VEGFR-2, may have pathways in RCC. PDGFR-α/β, Flt-3, activity in Possible activity c-Kit melanoma when against BRAF in combined with melanoma, colon chemotherapy cancer, and others. Erlotinib EGFR Non- Competitive(Tarceva) small cell lung inhibitor of the ATP cancer; binding site of the pancreatic EGFR. cancer Gefitinb EGFR Non- Inhibitor of(Iressa) small cell lung EGFR tyrosine kinase. cancer Bortezomib ...