Antibody Targeting GRP78 Enhances the Efficacy of Radiation Therapy in Human Glioblastoma and Non–Small Cell Lung Cancer Cell Lines and Tumor Models

Abstract

Non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) have poor median survival. NSCLC and GBM overexpress glucose regulated protein 78 (GRP78), which has a role in radioresistance and recurrence. In this study, we determined the effect of anti-GRP78 antibody and the combined effect of the anti-GRP78 antibody with ionizing radiation (XRT) on NSCLC and GBM cell lines both and NSCLC and GBM cancer cell lines were treated with anti-GRP78 antibodies and evaluated for proliferation, colony formation, cell death, and PI3K/Akt/mTOR signaling. The efficacy of anti-GRP78 antibodies on tumor growth in combination with XRT was determined in mouse xenograft models. GBM and NSCLC cells treated with anti-GRP78 antibodies showed attenuated cell proliferation, colony formation, and enhanced apoptosis. GBM and NSCLC cells treated with anti-GRP78 antibodies also showed global suppression of PI3K/Akt/mTOR signaling. Combining antibody with XRT resulted in significant tumor growth delay in both NSCLC and GBM heterotopic tumor models. Antibodies targeting GRP78 exhibited antitumor activity and enhanced the efficacy of radiation in NSCLC and GBM both and GRP78 is a promising novel target, and anti-GRP78 antibodies could be used as an effective cancer therapy alone or in combination with XRT. .

The Effect of Afatinib Treatment in Non-small Cell Lung Cancer Cells

“…Nevertheless, in accordance to our studies afatinib by itself induces apoptosis and mRNA level of HSPA5 decreases. On the other hand, a study by Dadey Dy et al showed that enhanced programmed cell death might be triggered by HSPA5 inhibition (16). In our results, it seems that apoptosis is caused by afatinib treatment and HSPA5 mRNA level reduction depends on morphological changes.…”

“…Next, we examined the levels of HSPA5 mRNA before and after treatment, since accessible information conferring the role of HSPA5 in NSCLC, particularly in programmed cell death, is still contradictory. According to some current results, NSCLC cells treated with anti-HSPA5 antibodies showed reduced cell proliferation, colony formation, and enhanced apoptosis (16). Moreover, the experiments conducted by other researchers revealed that HSPA5 up-regulation in A549 cells followed by cisplatin treatment leads to increased apoptosis.…”

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…Additionally, glucose regulated protein 78 (GRP78) interacts with α2-macroglobulin to activate AKT1 via PDK1, as well as mTOR to enhance cancer cell proliferation and radiotherapy resistance in GBM [31][32][33]. Anti-GRP 78 antibody can restore cancer cells to sensitivity to radiation therapy, which inhibits cell proliferation and enhances apoptosis, and has the advantage of targeting against cancer cells without affecting normal cells.…”

“…Anti-GRP 78 antibody can restore cancer cells to sensitivity to radiation therapy, which inhibits cell proliferation and enhances apoptosis, and has the advantage of targeting against cancer cells without affecting normal cells. Moreover, combination of anti-GRP 78 antibody and radiation therapy (XRT) shows better inhibitory effect on tumor [31].…”

Stressed Out - Therapeutic Implications of ER Stress Related Cancer Research

“…A monoclonal antibody against GRP78 was shown to suppress signaling through the PI3K/Akt/mTOR pathway, which is responsible for radiation resistance in non-small cell lung cancer and glioblastoma multiforme (GBM). They found that ionizing radiation increased GRP78 expression through the induction of ER stress, and treatment with the monoclonal antibody along with ionizing radiation in mouse xenograph models showed significant tumor growth delay[32]. The other recent therapeutic model utilized a phage, displaying a ligand specific to GRP78, to deliver the herpes simplex virus thymidine kinase type-1 suicide inducing transgene to mice with MDA-PCa-118b patient derived tumor xenografts.…”