title: A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies.
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.
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Irwin
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Blake P
authors.initials: BP
authors.lastname: Johnson
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Roxsan
authors.initials: R
authors.lastname: Manshouri
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.affiliation: Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: Joya
authors.initials: J
authors.lastname: Chandra
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology; D000069439:Dasatinib / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000473:pathology; D010084:Oxidation-Reduction; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000068877:Imatinib Mesylate; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C512478:EGFR protein, human; D066246:ErbB Receptors; C494957:FYN protein, human; D016044:Fusion Proteins, bcr-abl; D051076:Proto-Oncogene Proteins c-fyn; D000069439:Dasatinib
keywords: CML; Egr-1; Fyn; NOX; TKI-resistance