Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options

Sundaram, Daniel Nisakar Meenakshi; Jiang, Xiaoyan; Brandwein, Joseph; Valencia-Serna, Juliana; Remant, K C; Uludağ, Hasan

doi:10.1016/j.drudis.2019.05.007

Cited by 41 publications

(36 citation statements)

References 149 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Resistance to TKI in CML can lead to disease progression and relapse, especially in advanced stage (El Eit et al, 2019;Sundaram et al, 2019). The mechanism can be broadly classified as either Bcr-Abl-dependent or independent according to if the kinase domain was mutant or not (Ma et al, 2014;Mitchell et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

PKC‐β/Alox5 axis activation promotes Bcr‐Abl‐independent TKI‐resistance in chronic myeloid leukemia

Liu

Wang

et al. 2021

Journal Cellular Physiology

View full text Add to dashboard Cite

Bcr-Abl independent resistance to tyrosine kinase inhibitor (TKI) is a crucial factor lead to relapse or acute leukemia transformation in chronic myeloid leukemia (CML).However, its mechanism is still unclear. Herein, we found that of nine common protein kinases C (PKCs), PKC-β overexpression was significantly related with TKI resistance. Blockage of its expression in CD34+ cells and CML cell lines increased sensitivity to imatinib. Then, eighty-four leukemia related genes were compared between TKI-resistant CML cell lines with PKC-β silenced or not. Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that Arachidonate 5-lipoxygenase (Alox5) and its relative pathway mainly participated in the resistance induced by PKC-β overexpression. It's also observed that Alox5 was increased not only in bone marrow biopsy but also in CD34 + cells derived from IM-resistant CML patients. The signaling pathway exploration indicated that ERK1/2 pathway mediates Alox5 upregulation by PKC-β. Meanwhile, we also proved that Alox5 induces TKI-insensitivity in CML through inactivation of PTEN. In vivo experiment, PKC-β elective inhibitor LY333531 prolonged survival time in CML-PDX mice model. In conclusion, targeted on PKC-β overexpression might be a novel therapy mechanism to overcome TKI-resistance in CML.

show abstract

Section: Discussionmentioning

confidence: 99%

PKC‐β/Alox5 axis activation promotes Bcr‐Abl‐independent TKI‐resistance in chronic myeloid leukemia

Liu

Wang

et al. 2021

Journal Cellular Physiology

View full text Add to dashboard Cite

show abstract

“…Over 100 different mutations have been identified, affecting more than 50 amino acids [ 26 ]. The mechanism of action of these mutations includes decrease affinity of TKI to the binding domain or changes in BCR-ABL1 conformation [ 27 ]. The frequency of mutations increases with disease progression, occurring in approximately 75% of myeloid CML-blast crises (-BC) cases [ 14 ].…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

101

View full text Add to dashboard Cite

Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

show abstract

“…The latter is mainly affected by Bcr-Abl point mutation, p-loop mutation, and abnormal expression of Bcr-Abl gene (Kayastha et al, 2017;Zhao et al, 2010). Imatinib competitively binds to the binding site of ATP to the thymidine kinase (TPK) receptor on the Bcr-Abl protein, blocks Bcr-Abl tyrosine kinase activity, and inhibits downstream signal transduction, causing it to lose its catalysis effect (Sundaram et al, 2019). As the disease progresses, mutations have been emerged in Bcr-Abl kinase region that causing the resistance to imatinib in patients (Berman et al, 2016;Quintás-Cardama et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Recent advances in Bcr‐Abl tyrosine kinase inhibitors for overriding T315I mutation

et al. 2020

View full text Add to dashboard Cite

BCR-ABL is a gene produced by the fusion of the bcr gene and the c-abl protooncogene and is considered to be the main cause of chronic myelogenous leukemia (CML) production. Therefore, the development of selective Bcr-Abl kinase inhibitors is an attractive strategy for the treatment of CML. However, in the treatment of CML with a Bcr-Abl kinase inhibitor, the T315I gatekeeper mutant disrupts the important contact interaction between the inhibitor and the enzyme, resistant to the first-and second-generation drugs currently approved, such as imatinib, bosutinib, nilotinib, and dasatinib. In order to overcome this special resistance, several different strategies have been explored, and many molecules have been studied to effectively inhibit Bcr-Abl T315I. Some of these molecules are still under development, and some are being studied preclinically, and still others are in clinical research. Herein, this review reports some of the major examples of third-generation Bcr-Abl inhibitors against the T315I mutation.

show abstract

Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options

Cited by 41 publications

References 149 publications

PKC‐β/Alox5 axis activation promotes Bcr‐Abl‐independent TKI‐resistance in chronic myeloid leukemia

PKC‐β/Alox5 axis activation promotes Bcr‐Abl‐independent TKI‐resistance in chronic myeloid leukemia

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Recent advances in Bcr‐Abl tyrosine kinase inhibitors for overriding T315I mutation

Contact Info

Product

Resources

About