HSP90 inhibitors induce GPNMB cell-surface expression by modulating lysosomal positioning and sensitize breast cancer cells to glembatumumab vedotin

buir.contributor.authorTokat, Ünal Metin
buir.contributor.orcidTokat, Ünal Metin|0000-0003-0026-368X
dc.citation.epage1717en_US
dc.citation.spage1701en_US
dc.citation.volumeNumber41en_US
dc.contributor.authorBiondini, M.
dc.contributor.authorKiepas, A.
dc.contributor.authorEl-Houjeiri, L
dc.contributor.authorAnnis, M.G.
dc.contributor.authorHsu, B.E.
dc.contributor.authorFortier, A.M.
dc.contributor.authorMorin, G.
dc.contributor.authorMartina, J.A.
dc.contributor.authorSirois, I.
dc.contributor.authorAguilar-Mahecha, A.
dc.contributor.authorGruosso, T.
dc.contributor.authorMcGuirk, S
dc.contributor.authorRose, A.A.N.
dc.contributor.authorTokat, Ünal Metin
dc.contributor.authorJohnson, R.M.
dc.contributor.authorŞahin, Ö.
dc.contributor.authorBareke, E.
dc.contributor.authorSt-Pierre, J.
dc.contributor.authorPark, M.
dc.contributor.authorBasik, M.
dc.contributor.authorMajewski, J.
dc.contributor.authorPuertollano, R.
dc.contributor.authorPause, A.
dc.contributor.authorHuang, S.
dc.contributor.authorKeler, T.
dc.contributor.authorSiegel, P.M.
dc.date.accessioned2023-02-16T06:40:02Z
dc.date.available2023-02-16T06:40:02Z
dc.date.issued2022-02-02
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractTransmembrane glycoprotein NMB (GPNMB) is a prognostic marker of poor outcome in patients with triple-negative breast cancer (TNBC). Glembatumumab Vedotin, an antibody drug conjugate targeting GPNMB, exhibits variable efficacy against GPNMB-positive metastatic TNBC as a single agent. We show that GPNMB levels increase in response to standard-of-care and experimental therapies for multiple breast cancer subtypes. While these therapeutic stressors induce GPNMB expression through differential engagement of the MiTF family of transcription factors, not all are capable of increasing GPNMB cell-surface localization required for Glembatumumab Vedotin inhibition. Using a FACS-based genetic screen, we discovered that suppression of heat shock protein 90 (HSP90) concomitantly increases GPNMB expression and cell-surface localization. Mechanistically, HSP90 inhibition resulted in lysosomal dispersion towards the cell periphery and fusion with the plasma membrane, which delivers GPNMB to the cell surface. Finally, treatment with HSP90 inhibitors sensitizes breast cancers to Glembatumumab Vedotin in vivo, suggesting that combination of HSP90 inhibitors and Glembatumumab Vedotin may be a viable treatment strategy for patients with metastatic TNBC.en_US
dc.identifier.doi10.1038/s41388-022-02206-zen_US
dc.identifier.eissn1476-5594
dc.identifier.urihttp://hdl.handle.net/11693/111385
dc.language.isoEnglishen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofhttps://doi.org/10.1038/s41388-022-02206-zen_US
dc.source.titleOncogeneen_US
dc.titleHSP90 inhibitors induce GPNMB cell-surface expression by modulating lysosomal positioning and sensitize breast cancer cells to glembatumumab vedotinen_US
dc.typeArticleen_US
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