Abstract 4023: Inhitibing GRP78 in non-small cell lung cancer with acquired resistance to EGFR-TKI

Abstract

Abstract Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have improved the survival of non small cell lung cancer (NSCLC) patients with active mutation of EGFR. However, some of the patients who received EGFR-TKIs showed the acquired resistance, and eventually relapsed within several months. In the TCGA data sets, gene expression of glucose-related protein 78 (GRP78), an ER chaperone, was upregulated in NSCLC tissues. We also confirmed that protein level of GRP78 was increased in HCC827-GR, H1993-GR and H1993-ER NSCLC cell lines with acquired resistance to EGFR-TKIs. Since GRP78 modulates ER stress level which induces ROS and apoptosis, Ru(II) complex 1 and HA15, both the known GRP78 inhibitors induced higher ER stress and ROS generation accompanying more remarkable anti-proliferative and apoptotic effects in EGFR-TKI-resistant NSCLC cell lines. GRP78 level was also found to be higher in H1975, EGFR-TKI-resistant T790M-mutant cell line than other NSCLC cell lines. Blockade of GRP78 also led to apoptosis in H1975, which is consistent with the results found in the acquired EGFR-TKI-resistant cell lines. In summary, we suggest GRP78 targeting as a potential therapeutic strategy for the acquired EGFR-TKI-resistant NSCLC patients. Citation Format: Jaewoo Park, Baskaran Purushothaman, Sera Hong, Munkyung Choi, Joon Myong Song, Keon Wook Kang. Inhitibing GRP78 in non-small cell lung cancer with acquired resistance to EGFR-TKI. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4023.