Research Papers:
A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies
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Abstract
Mary E. Irwin1, Blake P. Johnson1,2, Roxsan Manshouri3, Hesham M. Amin3 and Joya Chandra1,2
1 Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 University of Texas Graduate School of Biomedical Sciences at Houston, TX, USA
3 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence to:
Joya Chandra, email:
Keywords: TKI-resistance, CML, NOX, Fyn, Egr-1
Received: April 14, 2015 Accepted: June 12, 2015 Published: June 23, 2015
Abstract
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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