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

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Toh SY, Leong HS, Chong FT, Rodrigues-Junior DM, Ren MJ, Kwang XL, Lau DPX, Lee PH, Vettore AL, Teh BT, Tan DSW, Iyer NG

Dev. Cell 59 (16) 2189-2202.e8 [2024-08-19; online 2024-07-31]

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.

PubMed 39089249

DOI 10.1016/j.devcel.2024.07.003

Crossref 10.1016/j.devcel.2024.07.003

pii: S1534-5807(24)00442-8