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

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.