1. Academic Validation
  2. GRP78 blockade overcomes acquired resistance to EGFR-tyrosine kinase inhibitors in non-small cell lung cancer

GRP78 blockade overcomes acquired resistance to EGFR-tyrosine kinase inhibitors in non-small cell lung cancer

  • Life Sci. 2024 Jul 1:348:122681. doi: 10.1016/j.lfs.2024.122681.
Jaewoo Park 1 Baskaran Purushothaman 1 Sera Hong 1 Munkyung Choi 1 Kyung Hwan Jegal 2 Miso Park 3 Joon Myong Song 4 Keon Wook Kang 5
Affiliations

Affiliations

  • 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 Department of Korean Medical Classics, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.
  • 3 College of Pharmacy, Kangwon National University, Chuncheon, Gangwon-do 24341, Republic of Korea.
  • 4 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: jmsong@snu.ac.kr.
  • 5 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: kwkang@snu.ac.kr.
Abstract

Aims: While significant upregulation of GRP78 has been documented in lung Cancer patients, its association with resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains underexamined. Our study aimed to elucidate the functional importance of GRP78 in acquired resistance to EGFR-TKIs in non-small cell lung Cancer (NSCLC) and to evaluate its potential as a therapeutic target.

Main methods: Immunoblot analysis or flow cytometry was employed to assess several markers for endoplasmic reticulum (ER) stress and Apoptosis. Ru(II) complex I and HA15, two known GRP78 inhibitors, were used to evaluate the functional role of GRP78. A Xenograft assay was performed to evaluate the in vivo anti-cancer effects of the GRP78 inhibitors.

Key findings: We validated a significant increase in GRP78 protein levels in HCC827-GR, H1993-GR, and H1993-ER cells. The EGFR-TKI-resistant cells overexpressing GRP78 exhibited significantly higher cell proliferation rates than did their parental counterparts. Notably, GRP78 inhibition resulted in a more profound anti-proliferative and apoptotic response via heightened ER stress and subsequent Reactive Oxygen Species (ROS) production in EGFR-TKI-resistant cell lines compared with their parental cells. In xenograft models implanted with HCC827-GR, both Ru(II) complex I and HA15 significantly suppressed tumor growth and reduced tumor weight. Additionally, we confirmed that GRP78 plays a critical role in the proliferation of H1975, an EGFR-TKI-resistant T790M-mutant cell line, relative to Other NSCLC cell lines.

Significance: Our findings strongly support targeting of GRP78 as a promising therapeutic strategy for NSCLC patients with acquired resistance to EGFR-TKIs.

Keywords

EGFR-TKI resistance; ER stress; GRP78; NSCLC; Therapeutic target.

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