Resistance in chronic myeloid leukemia: definitions and novel therapeutic agents

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Abstract

Purpose of review

Chronic myeloid leukemia (CML) is hallmarked by the presence of fusion protein kinase derived from a reciprocal translocation between chromosome 9 and 22, breakpoint cluster region (BCR)–Abelson leukemia virus (ABL) 1, causing aberrant regulation of the downstream pathways leading to unchecked CML leukemia stem cells (LSCs) proliferation. Since the discovery of tyrosine kinase inhibitors (TKI), CML, once a fatal disease, has become a chronic illness if managed appropriately. Changing treatment landscape has unsurfaced the challenge of TKI resistance that is clinically difficult to overcome.

Recent findings

In this review, we discuss the concept of TKI resistance and pathways leading to the resistance which allows for a survival advantage to CML LSCs. Aside from BCR–ABL-dependent mechanisms of resistance which involves aberrant expression in the regulatory pumps involving efflux and influx of the TKI affecting drug bioavailability, activation of alternate survival pathways may be accountable for primary or secondary resistance. Activation of these pathways, intrinsically and extrinsically to LSCs, may be mediated through various upstream and downstream signaling as well as conditions affecting the microenvironment. Several therapeutic approaches that combine TKI with an additional agent that inhibits the activation of an alternate pathway have been studied as part of clinical trials which we will discuss here.

Summary

We categorize the resistance into BCR–ABL-dependent and BCR–ABL-independent subgroups to further describe the complex molecular pathways which can potentially serve as a therapeutic target. We further discuss novel combination strategies currently in early or advanced phase clinical trials aimed to overcome the TKI resistance. We further highlight the need for further research despite the tremendous strides already made in the management of CML.

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