Mechanisms of resistance to BCR–ABL TKIs and the therapeutic strategies: A review

https://doi.org/10.1016/j.critrevonc.2014.11.001Get rights and content

Highlights

  • •

    The resistant mechanisms of BCR-ABL TKIs.

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    Strategies for overcoming BCR-ABL TKIs resistance.

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    Problems still exists.

Abstract

BCR–ABL caused by the translocation of t(9,22) with elevated tyrosine-kinase activity could induce leukemia in mice, which established BCR–ABL as the molecular pathogenic event in CML (Chronic myeloid leukemia). In recent years, a variety of tyrosine kinase inhibitors (TKIs) targeting at BCR–ABL specifically and effectively have been developed, which has fundamentally promoted the treatment of CML. However, the efficacy of TKIs was limited by its resistance induced by the development of kinase domain mutations and other mechanisms illustrated. In this review, we summarized BCR–ABL inhibitors approved by Food and Drug Administration (FAD), with the same concerns focus on the resistant mechanisms of BCR–ABL inhibitors and therapeutic resistant strategies.

Introduction

A reciprocal translocation between chromosomes 9 and 22 produces a Philadelphia chromosome which leads to the formation of the novel BCR–ABL fusion gene [1]. BCR–ABL is an active constitutive tyrosine kinase that activates multiple downstream signaling pathways resulting in the survival and proliferation of CML cells [2], [3] and leading to the myeloproliferation disorder of CML.

As the elaborate mechanisms of BCR–ABL are illustrated, several TKIs targeting at BCR–ABL have been synthesized and screened, and the introduction of these variety kinds of inhibitors have basically promoted the treatment of CML. There are many other BCR–ABL inhibitors, which have already been either applied in the clinical treatment with significant effects in certain malignancies or in the clinical trial, representing a revolutionary approach to cancer therapy.

Section snippets

Clinical importance of TKIs resistance

Majority of patients can expect normal life as long as they continually abide by BCR–ABL-inhibitor treatment, unfortunately, a multitude of patients develop TKI-resistance overtime. From this and other frontline clinical trials it is estimated that 20–30% of patients will develop either primary (failure to achieve a predetermined milestones) or secondary (loss of the response after initial achievement of predetermined milestones) TKIs resistance and do not respond optimally to TKIs therapy,

BCR–ABL and its signal transduction

In 1960, the Philadelphia chromosome was first described in cell cultures from CML patients. The BCR–ABL fusion gene leads to the production of an abnormal tyrosine kinase protein, resulting in the dysregulated downstream signaling pathways and the increased proliferation and survival of leukemic cells. First, the ABL-moiety kinase domain becomes very active in catalytic and phosphorylates a variety of different substrate proteins. Second, the BCR-moiety of the fusion contributes pivotal

BCR–ABL inhibitors

Up to now, there are three generation BCR–ABL inhibitors approved by FDA. Here is the elaborated common information of the BCR–ABL inhibitors in Table 1.

BCR–ABL inhibitor resistance mechnisms

By far, many TKIs-resistance mechanisms has been discovered which can be divided into two part, BCR–ABL-dependent and—independent mechanisms. BCR–ABL-dependent mechanisms include mutations and amplification of BCR–ABL, impaired signaling pathways; BCR–ABL independent mechanisms include drug efflux mediated ABC-transporters, micro environment which facilitate resistance and deficient BER (base excision repair) for choromosomal abnormalities (Fig. 2). Understanding the underlying causes of

Reversal strategies for BCR–ABL inhibitor resistance

Since resistance mechanisms have been elaborated in several ways, reversal strategies targeting at those mechanisms show a promising prospect. Importantly, some novel strategies of overcoming the resistance were developed and used in clinic. In addition, combination treatment also exhibit a longterm effect for BCR–ABL -inhibitor-resistant. Strategies for overcoming resistance of BCR–ABL inhibitors have been listed in Table 2.

Conclusion

Despite the clinical efficacy of the first-, second- and third-generation BCR–ABL inhibitors, many major problems persist: the long-term tolerability, the side effect induced by the inhibitors, the resistance to the inhibitors, the inability to eradicate CML stem cells and minimal residual disease. Fortunately, resistant mechanisms are illustrated in several ways and novel agents with theoretical good tolerability targeting multiple signaling pathways have been designed to sensitize cancer

Conflict of interest statement

The authors report no conflict of interest.

Reviewers

Professor Jin-ming Yang, MD, PhD: Dept of Pharmacology and the Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine500 University Drive, Hershey, PA 17033, USA.

Professor Xiang-Xi Mike Xu, PhD: School of Medicine, University of Miami, Miami FL 33136, USA.

Professor Jakob R Passweg, MD, MS: Hematology Division, Basel University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland.

Li-wu Fu MD, Ph.D., professor and director of Department of Experimental Research, Cancer Center, Sun Yat-sen University. He finished his Ph.D. program from Cancer Center, Sun Yat-sen University in 1996. And then he became a postdoctor in Medical University of South Carolina. He became a full professor in Cancer Center, Sun Yat-sen University in 2002. His major is Cancer Pharmacology. His active research field is cancer cell resistance and strategy.

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    Li-wu Fu MD, Ph.D., professor and director of Department of Experimental Research, Cancer Center, Sun Yat-sen University. He finished his Ph.D. program from Cancer Center, Sun Yat-sen University in 1996. And then he became a postdoctor in Medical University of South Carolina. He became a full professor in Cancer Center, Sun Yat-sen University in 2002. His major is Cancer Pharmacology. His active research field is cancer cell resistance and strategy.

    Ke Yang Ph.D. candidate. Her research dissertation field is leukemia resistance.

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