Proteolysis targeting chimera (PROTAC) for epidermal growth factor receptor enhances anti-tumor immunity in non-small cell lung cancer
DRUG DEVELOPMENT RESEARCH
Authors: Wang, Kai; Zhou, Hongping
Abstract
While immunotherapy has dramatically revolutionized the treatment of non-small cell lung cancer (NSCLC), it still faces challenges such as low therapeutic efficacy and immune-related adverse events, indicating that safe and effective approaches to enhance NSCLC immunotherapy are still highly demanded. Epidermal growth factor receptor (EGFR) is an established target for molecularly targeted therapy of NSCLC. Overexpression and activating mutations of EGFR can promote the resistance of NSCLC to immunotherapy via upregulating inhibitory immune checkpoints such as programmed death receptor ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase-1 (IDO1). Thus, therapeutic inhibition of EGFR also holds promise in modulating the immune microenvironment to advance NSCLC immunotherapy. In this study, we employed a proteolysis targeting chimera (PROTAC) that degrades EGFR(L858R) to investigate its potential in dually inhibiting PD-L1 and IDO1 to potentiate the anti-tumor immunity in NSCLC. We demonstrated that PROTAC significantly downregulated the protein levels of both PD-L1 and IDO1 in NSCLC H3255 cell and tumor. We also confirmed that PROTAC significantly suppressed the H3255 tumor growth and enhanced the anti-tumor immune response in H3255 tumor. Overall, our study provides a novel strategy for future NSCLC therapy.
Investigations of EGFR configurations on tumor cell surface by high-resolution electron microscopy
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Authors: Wang, Li; Li, Jintao; Zhang, Na; Zhang, Xiaofei; Xia, Yang; Chai, Binbin; Gao, Chunlang; Mao, Shengcheng; Ji, Yuan; Sheng, Wang; Han, Xiaodong
Abstract
Epidermal growth factor receptor (EGFR) is an important target for tumor therapy in various tumors. The current understanding of EGFR conformations on the cell surface is based on X-ray structural data, molecular dynamic simulations, and fluorescence-localization imaging. Using scanning electron microscope (SEM) and transmission electron microscope (TEM) with the resolution at sub-nanometers, we successfully recognized individual molecules of EGFRs and their assembly details on the surface of triple-negative breast cancer (TNBC) upon one-to-one labeling by Au nanoparticles. Based on our results, we have proposed the possible configurations, structural models, and conformational transitions of EGFR oligomers. Our study shows that the high-resolution electron imaging is an invaluable tool to provide direct evidence of EGFR configuration on tumor cell surfaces, and may play a pivotal role in further understanding of EGFR-associated signaling and tumor therapy. (C) 2020 Elsevier Inc. All rights reserved.
COA
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