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

Abstract

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.

• Authors: Marco Biondini, Alex Kiepas, Leeanna El-Houjeiri, Matthew G Annis, Brian E Hsu, Anne-Marie Fortier, Geneviève Morin, José A Martina, Isabelle Sirois, Adriana Aguilar-Mahecha, Tina Gruosso, Shawn McGuirk, April A N Rose, Unal M Tokat, Radia M Johnson, Ozgur Sahin, Eric Bareke, Julie St-Pierre, Morag Park, Mark Basik, Jacek Majewski, Rosa Puertollano, Arnim Pause, Sidong Huang, Tibor Keler, Peter M Siegel
• Journal: Oncogene (Oncogene) Vol. 41 Issue 12 Pg. 1701-1717 (03 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35110681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• GPNMB protein, human
• Immunoconjugates
• Membrane Glycoproteins
• Transcription Factors
• glembatumumab vedotin

Topics

• Antibodies, Monoclonal
• Antineoplastic Agents (therapeutic use)
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Humans
• Immunoconjugates (adverse effects)
• Lysosomes (metabolism)
• Membrane Glycoproteins (genetics)
• Transcription Factors
• Triple Negative Breast Neoplasms (drug therapy)