Imatinib (STI571) Resistance in Chronic Myelogenous Leukemia: Molecular Basis of the Underlying Mechanisms and Potential Strategies for Treatment

Abstract

Following the paradigm set by STI571, protein tyrosine kinase inhibitors are emerging as a promising class of drugs, capable of modulating intracellular signaling and demonstrating therapeutic potential for the treatment of proliferative diseases. Although the majority of chronic phase CML patients treated with STI571 respond, some patients, especially those with more advanced disease, relapse. This article reviews the reasons for relapse and, in particular, analyses resistance resulting from Bcr-Abl tyrosine kinase domain mutations at the molecular level. Arguments are based upon the structure of the STI571-Abl complex, which is compared to the crystal structures of PD173955-Abl and PD180970-Abl, which bind to the kinase differently. Strategies to potentially circumvent or overcome resistance are discussed.

Oligomerization inhibition, combined with allosteric inhibition, abrogates the transformation potential of T315I-positive BCR/ABL

“…7 These clones are selected by continuous exposure to ABL kinase inhibitors. 4,8 With the exception of the 'gatekeeper' mutation, T315I, the most clinically relevant mutations confer resistance against the first-generation ABL kinase inhibitor, imatinib, but can still be targeted using one of the second-generation ABL kinase inhibitors, dasatinib or nilotinib. 7 Tetramerization of ABL through the N-terminal coiled-coil region (CC) of BCR is essential for aberrant ABL-kinase activation.…”

Critical appraisal of nilotinib in frontline treatment of chronic myeloid leukemia

“…19 However, crystallographic studies have revealed an improved topological fit for the ABL protein. 20 This is due to the design of more potent compounds that incorporate alternative binding groups.…”

Causative Factors Involved in Development of Resistance to Tyrosine Kinase Inhibition and Novel Strategies Designed to Override This Resistance

“…Point mutations that reduce imatinib binding through a direct mechanism are generally positioned around the imatinib binding site, and diminish imatinib binding through alterations in amino acid side chains or topographical changes that sterically hinder the binding of imatinib. Phe317 and Thr315 are examples of this type of BCR-ABL point mutation (Cowan-Jacob et al, 2004). Point mutations that reduce imatinib binding through an indirect mechanism utilize the distinct binding mode of a drug to BCR-ABL.…”