期刊
ONCOTARGET
卷 6, 期 27, 页码 23631-23646出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4604
关键词
TKI-resistance; CML; NOX; Fyn; Egr-1
资金
- National Institutes of Health through MD Anderson's Cancer Center Support Grant [P30 CA016672]
- Brain Tumor SPORE [P50 CA127001, F32 CA171905, R01 CA151533, R01 CA115811]
- Center for Stem Cell and Developmental Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
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 overexpression 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 EGFR Delta III-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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