HER3 in breast cancer: molecular insights, clinical implications, and therapeutic horizons.

Abstract

Introduction: erb-b2 receptor tyrosine kinase 3 (ERBB3/HER3) a kinase-inactive HER family receptor, significantly influences breast cancer by enhancing oncogenic signaling mainly via HER2 heterodimerization. Its role in therapy resistance marks it as a key target across subtypes, tackling a critical oncology challenge.

Areas covered: This review delves into HER3's molecular structure, with its ligand-binding extracellular domain and tyrosine-rich tail activating PI3K/AKT and MAPK/ERK pathways. It examines HER3's impact on tumor progression - like invasion and metastasis - and resistance to therapies such as trastuzumab, endocrine treatments, and chemotherapy across HER2- positive, hormone receptor-positive, and triple-negative subtypes, based on extensive literature. Clinically, it assesses HER3's prognostic role, with overexpression in 30-50% of cases, and therapeutic advances, notably antibody-drug conjugates (ADCs) like patritumab deruxtecan, promising in trials.

Expert opinion: HER3's therapeutic potential is transformative, with ADCs and combinations poised to redefine personalized care by improving survival in resistant cases. Its overexpression offers a strategic leverage point, yet inconsistent detection and adaptive resistance pose barriers. These demand innovative solutions, such as refined diagnostics and multi-target therapies. Given its demonstrated efficacy, HER3-targeted therapies, supported by novel therapeutic combinations and bioengineering innovations, are expected to become integral to routine clinical practice in the coming years, advancing precision oncology.