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Dual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer

Authors
 Ye-Jin Kim  ;  Du-San Baek  ;  Seyoung Lee  ;  Daechan Park  ;  Han Na Kang  ;  Byoung Chul Cho  ;  Yong-Sung Kim 
Citation
 CANCER LETTERS, Vol.466 : 23-34, 2019 
Journal Title
 CANCER LETTERS 
ISSN
 0304-3835 
Issue Date
2019
Keywords
Bispecific antibody ; Cetuximab resistance ; EGFR/NRP1 dual-targeting ; Integrin β3 ; KRAS mutation
Abstract
The therapeutic targeting of oncogenic KRAS mutant-harboring (KRASMUT) non-small cell lung cancer (NSCLC) is an urgent unmet need in cancer therapy. Although NSCLC is often driven by epidermal growth factor receptor (EGFR) overexpression and/or mutations, no EGFR-targeted therapy is clinically available for KRASMUT NSCLC. In this study, we show that integrin β3 expression is associated with the intrinsic resistance of KRASMUT NSCLCs to the anti-EGFR antibody cetuximab. Further analyses identified an integrin β3-mediated ternary complex comprising NRP1-integrin β3-KRASMUT and its downstream signaling of PI3K-Akt and RalB-TBK1 as a primary resistance mechanism of KRASMUT NSCLC to cetuximab treatment. Importantly, we demonstrate that the EGFR/NRP1 dual-targeting bispecific antibody, Ctx-TPP11, attenuates the downstream signaling driven by the ternary complex via the cellular co-internalization and degradation of the NRP1-coupled complex, resulting in the alleviation of cetuximab resistance in KRASMUT NSCLCs in vitro and in vivo, including patient-derived xenograft mouse models. Our study shows that the dual-targeting of EGFR and NRP1 with a bispecific antibody might be an effective therapeutic strategy for KRASMUT NSCLC.
Full Text
https://www.sciencedirect.com/science/article/pii/S0304383519304690
DOI
10.1016/j.canlet.2019.09.005
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/174521
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