Mechanisms of Action of EGFR Tyrosine Kinase Receptor Incorporated in Extracellular Vesicles

Abstract

EGFR and some of the cognate ligands extensively traffic in extracellular vesicles (EVs) from different biogenesis pathways. EGFR belongs to a family of four homologous tyrosine kinase receptors (TKRs). This family are one of the major drivers of cancer and is involved in several of the most frequent malignancies such as non-small cell lung cancer, breast cancer, colorectal cancer and ovarian cancer. The carrier EVs exert crucial biological effects on recipient cells, impacting immunity, pre-metastatic niche preparation, angiogenesis, cancer cell stemness and horizontal oncogene transfer. While EV-mediated EGFR signalling is important to EGFR-driven cancers, little is known about the precise mechanisms by which TKRs incorporated in EVs play their biological role, their stoichiometry and associations to other proteins relevant to cancer pathology and EV biogenesis, and their means of incorporation in the target cell. In addition, it remains unclear whether different subtypes of EVs incorporate different complexes of TKRs with specific functions. A raft of high spatial and temporal resolution methods is emerging that could solve these and other questions regarding the activity of EGFR and its ligands in EVs. More importantly, methods are emerging to block or mitigate EV activity to suppress cancer progression and drug resistance. By highlighting key findings and areas that remain obscure at the intersection of EGFR signalling and EV action, we hope to cross-fertilise the two fields and speed up the application of novel techniques and paradigms to both.

Investigating the Mechanism of Guizhi Fuling Formula in the Treatment of Primary Dysmenorrhea based on Network Pharmacology and Molecular Docking

“…Epidermalgrowth factor receptor(EGFR) belongs to a family of four homologous tyrosine kinase receptors (TKRs). This family are one of the major drivers of cancer and is involved in several of the most frequent malignancies such as non-small cell lung cancer, breast cancer, colorectal cancer and ovarian cancer [42]. Although EGFR related to many diseases, there were not published trials con rmed the association between EGFR and PD.…”

Extracellular Vesicles: A Novel Tool Facilitating Personalized Medicine and Pharmacogenomics in Oncology

“…EGFR EVs release additionally responded to cetuximab, TKIs or temozolomide treatment of cells in vitro (Shao et al, 2012;Montermini et al, 2015;van Dommelen et al, 2016;Fujiwara et al, 2018). In vitro, EGFR EVs were shown to be involved in several cancer hallmarks like inducing angiogenesis, sustaining proliferating signaling, evading growth suppression and immune destruction, promoting inflammation, resisting cell death, and activating invasion and metastasis (reviewed in (Zanetti-Domingues et al, 2020)). Further studies on EVs as therapy delivery system are also needed, as EVs containing let-7a reduced tumor size in mice EGFR-expressing breast cancer model (Ohno et al, 2013).…”

Nasopharyngeal Carcinoma: The Role of the EGFR in Epstein–Barr Virus Infection

“…Then, EGFR-rich EVs promote EGFR up-regulation and intracellular ROS reduction through the EGFR/PI3K/Akt pathway, thus aggravating the metastasis and progression of NPC [ 81 ]. Undoubtedly, EVs delivering EGFR or EGFR ligands promote angiogenesis, metastasis, and osteoclastogenesis in tumors, modulating the immune system and blocking these EVs’ activities to reduce drug resistance [ 82 , 83 ]. Therefore, the EGFR may be a favorable indicator for the progression of NPC, which would be beneficial for exploiting new anti-metastatic medicine for advanced NPC therapies.…”