Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib

Tm, Kim; Sa, Ha; Hk, Kim; Yoo, Juhyun; S, Kim; Sh, Yim; Jung, Seung‐Hyun; Dw, Kim; Chung, Yeun‐Jun; Jw, Kim

doi:10.1038/bcj.2011.32

Cited by 20 publications

(14 citation statements)

References 38 publications

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“…JAG1 is part of the Notch signaling pathway and has been associated with disease progression and poor outcome in various cancer entities [170]. Interestingly, both JAG1 and miR-34-5p have already been demonstrated to influence drug resistance in other cancer entities [171,172], supporting the results of Ma et al [41].…”

Section: Dancrsupporting

confidence: 58%

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

Barth

Juráček

Slabý

et al. 2020

Cancers

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Available systemic treatment options for cancers of the genitourinary system have experienced great progress in the last decade. However, a large proportion of patients eventually develop resistance to treatment, resulting in disease progression and shorter overall survival. Biomarkers indicating the increasing resistance to cancer therapies are yet to enter clinical routine. Long non-coding RNAs (lncRNA) are non-protein coding RNA transcripts longer than 200 nucleotides that exert multiple types of regulatory functions of all known cellular processes. Increasing evidence supports the role of lncRNAs in cancer development and progression. Additionally, their involvement in the development of drug resistance across various cancer entities, including genitourinary malignancies, are starting to be discovered. Consequently, lncRNAs have been suggested as factors in novel therapeutic strategies to overcome drug resistance in cancer. In this review, the existing evidences on lncRNAs and their involvement in mechanisms of drug resistance in cancers of the genitourinary system, including renal cell carcinoma, bladder cancer, prostate cancer, and testicular cancer, will be highlighted and discussed to facilitate and encourage further research in this field. We summarize a significant number of lncRNAs with proposed pathways in drug resistance and available reported studies.

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Section: Dancrsupporting

confidence: 58%

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

Barth

Juráček

Slabý

et al. 2020

Cancers

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“…Following research confirmed that silencing of JAG1 blocks the metastasis of colorectal cancer and osteosarcoma via inactivation of the Notch pathway 27,28. Moreover, upregulation of JAG1 oncogene is observed in nilotinib and imatinib-resistant myeloblastic leukemia cells 29. miR-26b and miR-128 contribute to the resistance of nasopharyngeal carcinoma or glioma to cisplatin by downregulating JAG1 30,31.…”

Section: Discussionmentioning

confidence: 99%

<p>Long noncoding RNA DANCR contributes to docetaxel resistance in prostate cancer through targeting the miR-34a-5p/JAG1 pathway</p>

Ma¹,

Fan²,

Ren³

et al. 2019

OTT

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Background: Chemotherapy is one of the available options for prostate cancer (PC). However, the acquisition of chemoresistance has become a major cause of chemotherapy failure. The long noncoding RNA DANCR is demonstrated to serve as an oncogene in various human cancers, including PC. However, the potential role of DANCR in docetaxel (DTX) resistance of PC and its underlying mechanism remains unclear. Methods: The abundance of DANCR, miR-34a-5p, and JAG1 mRNA was examined by quantitative reverse transcription PCR. The Cell Counting Kit-8 (CCK8) was used to determine the 50% inhibitory concentration value. Cell viability was evaluated by CCK8 and colony-formation assays. Transwells were utilized to analyze cell migration and invasion ability. The protein levels of LRP, P-gp, MRP1, and JAG1 were measured by Western blot assay. The target relationship between DANCR and miR-34a-5p, as well as miR-34a-5p and JAG1, was demonstrated by dual-luciferase, RNA immunoprecipitation, and RNA pull-down analysis. Tumor xenograft was undertaken to confirm the effect of DANCR on DTX resistance in PC. Results: DANCR and JAG1 were significantly upregulated, but miR-34a-5p was downregulated in DTX-resistant PC. Silencing of DANCR improved the DTX efficacy in DTX-resistant PC cells. DANCR served as a competing endogenous RNA of miR-34a-5p, leading to the derepression of miR-34a-5p target JAG1, which eventually triggered the resistance to DTX in DTX-tolerated PC. Conclusion: The DANCR/miR-34a-5p axis enhanced DTX resistance of PC via targeting JAG1, providing a novel insight to improve chemotherapy for PC.

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“…Our lab has previously established that the Src family kinase Fyn is controlled by the elevated ROS levels in CML [ 37 ], and overexpression of Fyn has been suggested as a mediator of imatinib resistance in CML [ 38 – 40 ]. However, the source of ROS and pathway leading to elevated Fyn are unknown.…”

Section: Resultsmentioning

confidence: 99%

“…We and others have identified the Src family kinase Fyn as a potential redox-dependent mediator of TKI-resistance in CML [ 38 – 40 , 42 ]. Fyn is indeed up-regulated in TKI-resistant CML cell lines (Figure 2B ) however inhibition of Fyn kinase activity is insufficient to overcome pan-TKI-resistance (Figure 4A ).…”

Section: Discussionmentioning

confidence: 99%

A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies

et al. 2015

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Tyrosine kinase inhibitors (TKI) have improved CML response rates, and some are effective against resistance-promoting point mutations in BCR-ABL1. However, in the absence of point mutations, resistance still occurs. Here, we identify a novel pathway mediating resistance which connects p47phox, the organizer subunit of NADPH oxidase-2 (NOX2), with early growth response-1 (Egr-1) and the Src family kinase Fyn. We found up-regulation of p47phox, Egr-1, and Fyn mRNA and protein using paired isogenic CML cell lines and mined data. Isolation of CD34+ cells and tissue microarray staining from blast crisis CML patients confirmed in vivo over-expression of components of this pathway. Knockdown studies revealed that p47phox modulated reactive oxygen species and Egr-1 expression, which, in turn, controlled Fyn expression. Interestingly, Fyn knockdown sensitized TKI-resistant cells to dasatinib, a dual BCR-ABL1/Src inhibitor. Egr-1 knockdown had similar effects, indicating the utility of targeting Fyn expression over activation. Pointedly, p47phox knockdown also restored TKI-sensitivity, indicating that targeting the NOX2 complex can overcome resistance. The NOX2/Egr-1/Fyn pathway was also conserved within TKI-resistant EGFRΔIII-expressing glioblastoma and patient-derived glioblastoma stem cells. Thus, our findings suggest that targeting the NOX2/Egr-1/Fyn pathway may have clinical implications within multiple cancer types; particularly where efficacy of TKI is compromised.

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Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib

Cited by 20 publications

References 38 publications

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

<p>Long noncoding RNA DANCR contributes to docetaxel resistance in prostate cancer through targeting the miR-34a-5p/JAG1 pathway</p>

A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies

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