Cell surface GRP78: a potential mechanism of therapeutic resistant tumors

Abstract

GRP78 is a protein that acts as a chaperone within the endoplasmic reticulum (ER) and has multiple functions. It is induced by stress and abets cells from survival. Despite, multiple Stress conditions like ER, chronic psychological and nutritional stress, hypoxia, chemotherapy, radiation therapy, and drug resistance induce cell surface GRP78 (CS-GRP78) expression in cancer cells. Further, CS-GRP78 is associated with increased malignancy and resistance to anti-cancer therapies and is considered a high-value druggable target. Recent preclinical research suggests that targeting CS-GRP78 with anti-GRP78 monoclonal antibodies (Mab) in combination with other agents may be effective in reversing the failure of chemotherapy, radiotherapy, or targeted therapies and increasing the efficacy of solid tumors treatment. This article will review recent evidence on the role of CS-GRP78 in developing resistance to anti-cancer treatments and the potential benefits of combining anti-GRP78 Mab with other cancer therapies for specific patient populations. Furthermore, our limited understanding of how CS-GRP78 regulated in human studies is a major drawback for designing effective CS-GRP78-targeted therapies. Hence, more research is still warranted to translate these potential therapies into clinical applications.

Keywords: C38 monoclonal antibody; CS-GRP78; Chemoresitance; Drug resistance; ER-stress; Radioresistance; anti-GRP78 autoantibody.

Fig. 1

CS-GRP78 mediates resistance to chemotherapy and creating opportunities for combination therapy. Chemotherapy drugs induces cell surface expression of GRP78 and several other stress proteins and functions as coreceptors or ligands. Chemoresistance appears to be reinforced by CS-GRP78 through common downstream signaling pathways, such as RAS/MAPK and PI3K/AKT. Targeting CS-GRP78 with anti-GRP78 Mab is the most promising strategy to enhance anticancer activity and aid chemotherapy resistance

Fig. 2

Radioresistance mechanisms involving the CS-GRP78 axis and their therapeutic strategies. (A) Radiation therapy further elevates cell surface expression of GRP78 level in resistant cancer cells and can also transfer GRP78 to non-irradiated cells through EVs to increase radio resistance through metastasis. Further investigation is required to understand the molecular mechanism by which radiation induces the translocation of GRP78 to the cell surface. (B) Illustrations summarizing the main interplay and radioresistance mechanism involving the CS-GRP78 signaling axis. (C) The CS-GRP78 targeting method utilizes a unique recombinant peptide and paclitaxel-containing nanoparticle that specifically target tumors that have been irradiated, resulting in higher levels of apoptosis and a greater delay in tumor growth compared to conventional chemotherapy approaches