HER2/neu as a Signaling and Therapeutic Marker in Uterine Serous Carcinoma

Abstract

Research into aggressive gynecologic cancers such as uterine serous carcinoma (USC) has recently evolved from chemotherapy to the development of drugs targeting specific biomarkers differentially expressed/active in tumor cells. One such target is HER2/neu, which plays an important role in the coordination of cell growth and differentiation. Importantly, when overexpressed and/or amplified in tumor cells, the downstream tyrosine kinase of HER2/neu becomes constitutively activated, causing dysregulated gene transcription. In breast cancer patients, HER2/neu has been successfully utilized for many years as a target for multiple monoclonal antibodies and more recently antibody-drug conjugates (ADCs). Use in gynecologic malignancies has been slower, however, due to recently identified unique characteristics of HER2/neu protein expression and gene amplification in biologically aggressive tumors such as USC including its major heterogeneity and lack of apical staining when compared to breast cancer. Accordingly, the use of optimal testing algorithms for HER2/neu status in patients with USC may have important implications for the development of novel, effective, and targeted treatment modalities against this lethal variant of endometrial cancer. In this review, we discuss HER2/neu gene expression in USC, evaluate the efficacy of HER2/neu-directed therapies in both preclinical and clinical settings, and discuss possible mechanisms of resistance to HER2/neu targeting agents.

Keywords: HER2/neu; T-DM1; T-DXd; antibody-drug conjugates; pertuzumab; trastuzumab; uterine serous carcinoma.

Figure 1

HER2 signaling diagram. HER2 is at the center of EGFR signaling at the cell membrane level. Formation of homodimers or heterodimers with the other members of the EGFR family allows for transphosphorylation of the intracellular domains and signal transduction to the cytosol. The most studied pathways downstream of HER2 are the RAS/RAF/MEK/ERK and the PI3K/AKT/mTOR pathways. Once the signal reaches the nucleus, it is eventually translated into increased proliferation, survival, and invasion.