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.

使用酪氨酸激酶抑制剂 (TKI) 靶向野生型表皮生长因子受体 (EGFR) 从未在头颈鳞状细胞癌等癌症中取得预期的成功，这些癌症很大程度上依赖于 EGFR。我们之前已经证明，对 TKI 具有特殊反应的患者存在基因畸变，导致 EGFR 剪接变体 D 同工型 (IsoD) 过度表达。 IsoD 缺乏完整的跨膜和激酶结构域，在 TKI 敏感的患者来源培养物中的细胞外囊泡 (EV) 中分泌。值得注意的是，对 TKI 的精致敏感性可以转移到 TKI 耐药肿瘤细胞中，并且 EV 中的 IsoD 蛋白对于在体外和体内跨多种模型和药物转移表型是必要且充分的。这种药物反应需要完整的内吞机制，与全长 EGFR 结合，并通过内体区室中的 Src 磷酸化发出信号。我们提出了一种使用含有 EGFR I​​soD 的 EV 作为联合药物的治疗策略，以将 TKI 疗法的使用范围扩大到 EGFR 驱动的癌症。