PMID- 35798841
OWN - NLM
STAT- MEDLINE
DCOM- 20220711
LR  - 20220915
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 12
IP  - 1
DP  - 2022 Jul 7
TI  - Synchronous intracellular delivery of EGFR-targeted antibody-drug conjugates by 
      p38-mediated non-canonical endocytosis.
PG  - 11561
LID - 10.1038/s41598-022-15838-8 [doi]
LID - 11561
AB  - Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), 
      including cetuximab and panitumumab, have been used in clinic settings to treat 
      cancer. They have also recently been applied to antibody-drug conjugates (ADCs); 
      however, their clinical efficacy is limited by several issues, including lower 
      internalization efficiency. The binding of cetuximab to the extracellular domain 
      of EGFR suppresses ligand-induced events; therefore, we focus on 
      ligand-independent non-canonical EGFR endocytosis for the delivery of ADCs into 
      cells. Tumor necrosis factor-alpha (TNF-alpha) strongly induces the endocytosis of the 
      cetuximab-EGFR complex within 15 min via the p38 phosphorylation of EGFR in a 
      tyrosine kinase-independent manner. A secondary antibody conjugated with saporin, 
      a ribosome-inactivating protein, also undergoes internalization with the complex 
      and enhances its anti-proliferative activity. Anti-cancer agents, including 
      cisplatin and temozolomide, also induce the p38-mediated internalization. The 
      results of the present study demonstrate that synchronous non-canonical EGFR 
      endocytosis may be a feasible strategy for promoting the therapeutic efficacy of 
      EGFR-targeting ADCs in clinical settings.
CI  - (c) 2022. The Author(s).
FAU - Takahashi, Jun-Ichiro
AU  - Takahashi JI
AD  - Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University 
      of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
FAU - Nakamura, Shiori
AU  - Nakamura S
AD  - Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University 
      of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
FAU - Onuma, Iimi
AU  - Onuma I
AD  - Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University 
      of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
FAU - Zhou, Yue
AU  - Zhou Y
AD  - Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University 
      of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
FAU - Yokoyama, Satoru
AU  - Yokoyama S
AD  - Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University 
      of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
FAU - Sakurai, Hiroaki
AU  - Sakurai H
AD  - Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University 
      of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan. hsakurai@pha.u-toyama.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220707
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Immunoconjugates)
RN  - 0 (Ligands)
RN  - 0 (Pharmaceutical Preparations)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - PQX0D8J21J (Cetuximab)
SB  - IM
MH  - *Antineoplastic Agents/pharmacology/therapeutic use
MH  - Cell Line, Tumor
MH  - Cetuximab/chemistry/pharmacology
MH  - Endocytosis
MH  - ErbB Receptors/metabolism
MH  - *Immunoconjugates/pharmacology
MH  - Ligands
MH  - Pharmaceutical Preparations
PMC - PMC9262980
COIS- The authors declare no competing interests.
EDAT- 2022/07/08 06:00
MHDA- 2022/07/12 06:00
PMCR- 2022/07/07
CRDT- 2022/07/07 23:28
PHST- 2022/02/12 00:00 [received]
PHST- 2022/06/30 00:00 [accepted]
PHST- 2022/07/07 23:28 [entrez]
PHST- 2022/07/08 06:00 [pubmed]
PHST- 2022/07/12 06:00 [medline]
PHST- 2022/07/07 00:00 [pmc-release]
AID - 10.1038/s41598-022-15838-8 [pii]
AID - 15838 [pii]
AID - 10.1038/s41598-022-15838-8 [doi]
PST - epublish
SO  - Sci Rep. 2022 Jul 7;12(1):11561. doi: 10.1038/s41598-022-15838-8.