Glucose-regulated protein 78 (GRP78) as a potential novel biomarker and therapeutic target in multiple myeloma

ABSTRACT

Introduction

Glucose-regulated protein 78 (GRP78) is a stress-inducible molecular chaperone expressed within the endoplasmic reticulum where it acts as a master regulator of the unfolded protein response (UPR) pathway. At times of ER stress, activation of the UPR, a multimolecular pathway, limits proteotoxicity induced by misfolded proteins. In malignancies, including multiple myeloma which is characterized by an accumulation of misfolded immunoglobulins, GRP78 expression is increased, with notable translocation of GRP78 to the cell surface. Studies suggest cell-surface GRP78 (csGRP78) to be of prognostic significance with emerging evidence that it interacts with a myriad of co-ligands to activate signaling pathways promoting cell proliferation and survival or apoptosis.

Areas covered

This review focuses on the role of ER and csGRP78 in physiology and oncogenesis in multiple myeloma, addressing factors that shift the balance in GRP78 signaling from survival to apoptosis. The role of GRP78 as a potential prognostic biomarker is explored and current therapeutics in development aimed at targeting csGRP78 are addressed. We conducted a PubMed literature search using the keywords ‘GRP78,’ ‘multiple myeloma’ reviewing studies prior to 2020.

Expert opinion

Cell-surface GRP78 expression is a potential novel prognostic biomarker in myeloma and targeting of csGRP78 is promising and requires further investigation.

KEYWORDS:

• Biomarker
• ER stress
• glucose-regulated protein 78 (GRP78)
• multiple myeloma
• therapeutic target

Article highlights box

• GRP78 is an ubiquitously expressed ER molecular chaperone which at times of cellular stress acts to limit cellular proteotoxicity through activation of the unfolded protein response (UPR) pathway.

• The significance and abundance of cell-surface GRP78 (csGRP78) in normal physiology is uncertain with cell-surface presence reliant on interaction with other cell-surface proteins.

• Over-expression of ER and csGRP78 is recognized in various malignancies including myeloma.

• csGRP78 interacts with various co-ligands on the tumor cell membrane promoting distinct and possibly opposing outcomes.

• csGRP78 expression is also prominent on tumor microenvironment (TME) cells including cells of the immune system and endothelial cells.

• In myeloma, a malignancy characterized by excessive protein production, plasma cell and TME csGRP78 expression appears higher in patients with newly diagnosed and relapsed/refractory disease compared to patients with MGUS, a pre-malignant precursor condition.

• Higher intensity of csGRP78 expression appears to correlate with poor response to second-generation proteasome inhibitors and may act as a predictive biomarker.

• Inhibition of GRP78 sensitizes myeloma cells to proteasome inhibition leading to intense interest in combination therapy.

• Early phase clinical studies with a fully human, naturally occurring monoclonal antibody against GRP78 demonstrate a favorable safety profile and modest activity as monotherapy.

• Targeting the synthesis, stability, or activity of ER GRP78 directly or small molecule inhibition of the UPR is likely to lead to on-target but off-tumor side effects.

• Strategies to target tumor csGRP78 directly are in development and include monoclonal antibodies, recombinant proapoptotic ligands, and peptide- or antibody-drug conjugates.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.