HER3 beyond the canonical paradigm: a versatile signaling hub in oncogenesis and therapeutic resistance
HER3 functions as a versatile signaling hub beyond its canonical heterodimeric role, driving therapeutic resistance across multiple cancer types through non‑canonical interactions with non‑EGFR receptor tyrosine kinases, nuclear transcriptional regulation, and tumor microenvironment modulation.
Human epidermal growth factor receptor 3 (HER3/ErbB3) is classically recognized as a kinase‑impaired member of the epidermal growth factor receptor (EGFR) family, which can initiate oncogenic signaling by heterodimerizing with family members. However, the emerging drug resistance issues of HER-targeted therapies have urged researchers to decipher the role of HER3 as a versatile signaling hub, which is beyond its canonical paradigm. This review delineates the non‑canonical landscape of HER3, including its non‑EGFR family heterodimerization partners (e.g., MET, FGFR, IGF1R, AXL), its role as a transcriptional co‑regulator in the nucleus, and its contributions to metabolic reprogramming and the tumor microenvironment. These non‑canonical mechanisms collectively contribute to adaptive resistance to radiotherapy, chemotherapy, and immunotherapy, underscoring the need for next‑generation HER3‑targeted strategies.
Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.
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