Show simple item record

dc.contributor.authorJaiswal, A
dc.contributor.authorMurakami, K
dc.contributor.authorElia, A
dc.contributor.authorShibahara, Y
dc.contributor.authorDone, SJ
dc.contributor.authorWood, SA
dc.contributor.authorDonato, NJ
dc.contributor.authorOhashi, PS
dc.contributor.authorReedijk, M
dc.description.abstractTriple-negative breast cancer (TNBC) is a breast cancer subtype that lacks targeted treatment options. The activation of the Notch developmental signaling pathway, which is a feature of TNBC, results in the secretion of proinflammatory cytokines and the recruitment of protumoral macrophages to the tumor microenvironment. While the Notch pathway is an obvious therapeutic target, its activity is ubiquitous, and predictably, anti-Notch therapies are burdened with significant on-target side effects. Previously, we discovered that, under conditions of cellular stress commonly found in the tumor microenvironment, the deubiquitinase USP9x forms a multiprotein complex with the pseudokinase tribbles homolog 3 (TRB3) that together activate the Notch pathway. Herein, we provide preclinical studies that support the potential of therapeutic USP9x inhibition to deactivate Notch. Using a murine TNBC model, we show that USP9x knockdown abrogates Notch activation, reducing the production of the proinflammatory cytokines, C-C motif chemokine ligand 2 (CCL2) and interleukin-1 beta (IL-1β). Concomitant with these molecular changes, a reduction in tumor inflammation, the augmentation of antitumor immune response, and the suppression of tumor growth were observed. The pharmacological inhibition of USP9x using G9, a partially selective, small-molecule USP9x inhibitor, reduced Notch activity, remodeled the tumor immune landscape, and reduced tumor growth without associated toxicity. Proving the role of Notch, the ectopic expression of the activated Notch1 intracellular domain rescued G9-induced effects. This work supports the potential of USP9x inhibition to target Notch in metabolically vulnerable tissues like TNBC, while sparing normal Notch-dependent tissues.en_US
dc.publisherProceedings of the National Academy of Sciencesen_US
dc.relation.ispartofjournalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subject.fieldofresearchOncology and carcinogenesisen_US
dc.subject.fieldofresearchClinical pharmacology and therapeuticsen_US
dc.titleTherapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast canceren_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationJaiswal, A; Murakami, K; Elia, A; Shibahara, Y; Done, SJ; Wood, SA; Donato, NJ; Ohashi, PS; Reedijk, M, Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer, Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (38), pp. e2101592118en_US
gro.hasfulltextNo Full Text
gro.griffith.authorWood, Stephen A.

Files in this item


There are no files associated with this item.

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record