New Insights into the Molecular Resistance Mechanisms of Chronic Myeloid Leukemia

Author(s): Rui Huang, Qian Kang, Huimin Liu, Yuhua Li.

Journal Name: Current Cancer Drug Targets

Volume 16 , Issue 4 , 2016

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Abstract:

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the causative oncoprotein BCR-ABL1 (Breakpoint-cluster region/Abelson kinase), which is a fusion protein with constitutive tyrosine kinase activity. The first tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of CML. Despite the spectacular effects of imatinib, primary and acquired resistance as well as intolerance to imatinib still exist. The mechanisms of BCR-ABL1 point mutations, amplification of the BCR-ABL1 gene and increased expression of efflux drug transporters, which play important roles in resistance, have been extensively described. Consequently, second- and third-generation TKIs have been explored to overcome resistance. However, some CML patients are refractory to all available TKIs. In addition, most patients relapse after discontinuing TKI therapy, due to the existence of CML stem cells, which have been demonstrated to be primarily resistant to TKIs. Thus, TKIs alone are not sufficient to cure CML, and it is necessary to further investigate the molecular resistance mechanisms in both the bulk and stem cells of CML to identify new targets to overcome resistance and eradicate the residual CML stem cells. This article reviews new insights into the various molecular resistance mechanisms of CML and discusses treatment strategies based on the targets that have recently been found to play an important role in the molecular mechanisms of resistance.

Keywords: Chronic myeloid leukemia, mechanism, resistance, strategy, tyrosine kinase inhibitor, target therapy.

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Article Details

VOLUME: 16
ISSUE: 4
Year: 2016
Page: [323 - 345]
Pages: 23
DOI: 10.2174/1568009615666150921141004
Price: $58

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