HER3 beyond the canonical paradigm: a versatile signaling hub in oncogenesis and therapeutic resistance

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 emerges have urged researchers to decipher the role of HER3 as a versatile signaling hub, which is beyond its canonical paradigm. This review delineated the non-canonical landscape of HER3, providing a specialized dissection of its roles which distinguished from the general overviews. We summarized the non-EGFR family heterodimerization partners for HER3 (e.g. MET, FGFR, and IGF1R) and its unique role as a transcriptional co-regulator in the nucleus, and discussed the clinical conundrum regarding its divergent prognostic roles in different cancer types. By integrating the cutting-edge findings in recent years, this review presented the pivotal role of tumor cells hijacking HER3 to achieve metabolic reprogramming and the regulation of tumor microenvironment. These non-canonical mechanisms of HER3 collectively contribute to the adaptive resistance to radiotherapy, chemotherapy, and immunotherapy. By integrating current insights and analyzing unresolved paradoxes in published data, this review elaborated the versatile roles of HER3, and constructed a novel theoretical framework to lay foundation for conquering the challenges of therapeutic resistance in precision oncology by developing next-generation HER3-targeted strategies.