Therapeutic application of extracellular vesicular EGFR isoform D as a co-drug to target squamous cell cancers with tyrosine kinase inhibitors.

Autor:	Toh SY; Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore; Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore., Leong HS; Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore; Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore., Chong FT; Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore; Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore., Rodrigues-Junior DM; Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden., Ren MJ; Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore; Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore., Kwang XL; Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore., Lau DPX; Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore., Lee PH; Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore, Singapore., Vettore AL; Department of Biological Sciences, Universidade Federal de São Paulo, Diadema, Brazil., Teh BT; Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore, Singapore., Tan DSW; Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore., Iyer NG; Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore; Academic Clinical Program in Oncology, Duke-NUS Medical School, Singapore, Singapore; Department of Head and Neck Surgery, National Cancer Centre Singapore, Singapore, Singapore. Electronic address: gmsngi@nus.edu.sg.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2024 Aug 19; Vol. 59 (16), pp. 2189-2202.e8. Date of Electronic Publication: 2024 Jul 31.
DOI:	10.1016/j.devcel.2024.07.003
Abstrakt:	Targeting wild-type epidermal growth factor receptor (EGFR) using tyrosine kinase inhibitors (TKIs) never achieved its purported success in cancers such as head and neck squamous cell carcinoma, which are largely EGFR-dependent. We had previously shown that exceptional responders to TKIs have a genetic aberration that results in overexpression of an EGFR splice variant, isoform D (IsoD). IsoD lacks an integral transmembrane and kinase domain and is secreted in extracellular vesicles (EVs) in TKI-sensitive patient-derived cultures. Remarkably, the exquisite sensitivity to TKIs could be transferred to TKI-resistant tumor cells, and IsoD protein in the EV is necessary and sufficient to transfer the phenotype in vitro and in vivo across multiple models and drugs. This drug response requires an intact endocytic mechanism, binding to full-length EGFR, and signaling through Src-phosphorylation within the endosomal compartment. We propose a therapeutic strategy using EVs containing EGFR IsoD as a co-drug to expand the use of TKI therapy to EGFR-driven cancers. Competing Interests: Declaration of interests N.G.I. has/had a consulting or advisory role in PairX Therapeutics, Verimmune therapeutics, and Invivo surgical; received honoraria from Agilent, and research funding from Merck, all of which are outside this submitted work. D.S.W.T. received honoraria from Bristol-Myers Squibb, Takeda Pharmaceuticals, Novartis, Roche, and Pfizer; has consulting or advisory role in Novartis, Merck, Loxo Oncology, AstraZeneca, Roche, and Pfizer and received research funding from Novartis (Inst), GlaxoSmithKline (Inst), and AstraZeneca (Inst), outside this submitted work. N.G.I., D.S.W.T., S.Y.T., H.S.L., F.T.C., and D.M.R.-J. are listed as co-inventors on the patent application entitled “Method of Modulating Sensitivity To Tyrosine Kinase Inhibitor” (International Publication: WO2022045976A1), which describes a significant proportion of the data here. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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