HSP90 inhibitors induce GPNMB cell-surface expression by modulating lysosomal positioning and sensitize breast cancer cells to glembatumumab vedotin.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
11
08
2021
accepted:
20
01
2022
revised:
29
12
2021
pubmed:
4
2
2022
medline:
3
5
2022
entrez:
3
2
2022
Statut:
ppublish
Résumé
Transmembrane 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.
Identifiants
pubmed: 35110681
doi: 10.1038/s41388-022-02206-z
pii: 10.1038/s41388-022-02206-z
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antineoplastic Agents
0
GPNMB protein, human
0
Immunoconjugates
0
Membrane Glycoproteins
0
Transcription Factors
0
glembatumumab vedotin
1568H6A58U
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1701-1717Subventions
Organisme : CIHR
ID : PJT-153327
Pays : Canada
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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