GRP94/gp96 in Cancer: Biology, Structure, Immunology, and Drug Development

Abstract

As an endoplasmic reticulum heat-shock protein 90 (HSP90) paralog, GRP94 (glucose-regulated protein 94)/gp96 (hereafter referred to as GRP94) has been shown to be an essential master chaperone for multiple receptors including Toll-like receptors, Wnt coreceptors, and integrins. Clinically, expression of GRP94 correlates with advanced stage and poor survival in a variety of cancers. Recent preclinical studies have also revealed that GRP94 expression is closely linked to cancer growth and metastasis in melanoma, ovarian cancer, multiple myeloma, lung cancer, and inflammation-associated colon cancer. Thus, GRP94 is an attractive therapeutic target in a number of malignancies. The chaperone function of GRP94 depends on its ATPase domain, which is structurally distinct from HSP90, allowing design of highly selective GRP94-targeted inhibitors. In this chapter, we discuss the biology and structure-function relationship of GRP94. We also summarize the immunological roles of GRP94 based on the studies documented over the last two decades, as these pertain to tumorigenesis and cancer progression. Finally, the structure-based rationale for the design of selective small-molecule inhibitors of GRP94 and their potential application in the treatment of cancer are highlighted.

Keywords: ATPase; Chaperone; HSP90; Immune surveillance; Inhibitor.