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Chapter 46: Targeted Anticancer Therapies

An important mechanism by which clinical resistance develops to imatinib in chronic myelogenous leukemia is

a. increased excretion in the urine.

b. increased hepatic metabolism.

c. decreased bioactivation in cancer cells.

d. spontaneous mutations in the BCR-ABL kinase.

e. increased efflux from tumor cells.

Answer is d. The most important mechanism of acquired resistance to imatinib and other tyrosine kinase inhibitors arises from point mutations in the kinase domain of BCR-ABL. Molecular studies of circulating tumor cells have detected resistance-mediating kinase mutations prior to initiation of therapy, particularly in patients with Ph+ acute lymphoblastic leukemia (ALL) or CML in blastic crisis. This finding strongly supports the hypothesis that drug-resistant cells arise through spontaneous mutation and expand under the selective pressure of drug exposure. Mutations may become detectable in the peripheral blood of patients receiving imatinib in the accelerated phase and in the late (>4 years from diagnosis) chronic phase of CML, heralding the onset of drug resistance.

Mechanisms other than BCR-ABL kinase mutation play a minor role in resistance to imatinib. Amplification of the wild-type kinase gene, leading to overexpression of the enzyme, has been identified in tumor samples from patients resistant to treatment. The multidrug resistant (MDR) gene, which codes for a drug efflux protein, confers resistance experimentally but has not been implicated in clinical resistance.

The molecular target of trastuzumab is


b. VEGF.

c. ErbB1.

d. ErbB2.

e. CD20.

Answer is d. Trastuzumab is a humanized monoclonal antibody that binds to the external domain of HER2/neu (ErbB2).

Rituximab is approved as a single agent for relapsed indolent lymphomas. Its molecular target is

a. the CD20 antigen on B cells.

b. the CD52 antigen on B cells.

c. the CD33 antigen on B cells and other hematopoietic cells.

d. BCR-ABL in lymphoblasts.

e. the IL-2 receptor on T cells.

Answer is a. Rituximab is a chimeric monoclonal antibody that targets the CD20 B-cell antigen (Tables 46-1 and 46-2). CD20 is found on cells from the pre–B cell stage through its terminal differentiation to plasma cells and is expressed on 90% of ...

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