HER3 signaling and targeted therapy in cancer

Abstract

ERBB family members including epidermal growth factor receptor (EGFR) also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance. Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs). Studies also implicate HER3 contributing significantly to treatment failure, mostly through the activation of PI3K/AKT, MAPK/ERK and JAK/STAT pathways. Moreover, activating mutations in HER3 have highlighted the role of HER3 as a direct therapeutic target. Therapeutic targeting of HER3 includes abrogating its dimerization partners’ kinase activity using small molecule inhibitors (lapatinib, erlotinib, gefitinib, afatinib, neratinib) or direct targeting of its extracellular domain. In this review, we focus on HER3-mediated signaling, its role in drug resistance and discuss the latest advances to overcome resistance by targeting HER3 using mono- and bispecific antibodies and small molecule inhibitors.

Molecular Targeting Therapy against EGFR Family in Breast Cancer: Progress and Future Potentials

“…MM-111 is a bispecific antibody that simultaneously binds to Her3 and Her2 and results in an inhibition of the PI3K/pathway [85]. The safety and clinical effect of MM-111 combined with Trastuzumab are now being investigated in Her2 + and NRG + breast cancer in a different phase I/II clinical trial [86].…”

“…As EGFRs are involved in cellular transformation, a number of small molecule inhibitors binding to the receptor tyrosine kinases have been developed (Table 1). Although mAbs achieve higher success rates in clinical trials when compared to tyrosine kinase inhibitors (TKIs) and also show a higher specificity as well as a lower toxicity, their production costs are higher and they can only inhibit extracellular targets, whereas the tyrosine kinase inhibitors can target both intra-and extracellular domains of EGFRs [86].…”

Benefit of Later-Time-Point PET Imaging of HER3 Expression Using Optimized Radiocobalt-Labeled Affibody Molecules

“…2020, 21, 1972 2 of 16 activates the potent PI3K/AKT/mTor signaling pathway, affecting cell proliferation and survival [1], and upregulation of HER3 can be a bypass mechanism for signaling loss of other HER-family members due to HER-targeted therapy [4,5]. Co-expression of HER3 is, therefore, considered a cause for the development of therapy resistance, which has, for instance, been documented for the tyrosine kinase inhibitors (TKIs) lapatinib and gefitinib, targeting epidermal growth factor receptor (EGFR) and HER2 [6][7][8]. Thus, inhibition of HER3-mediated signaling might have potential to overcome therapy resistance [4,9] and monitoring of HER3 expression could, therefore, aid strategic decision making for cancer therapy.…”

Quantitative phosphoproteomics to unravel the cellular response to chemical stressors with different modes of action

“…CDDP treatment significantly upregulated phosphatase Ppp2r2a (also known as B55A), death-associated protein kinase Dapk1 as well as Mapk1/2 kinases that are stimulated upon extra-and intracellular signals. Exclusive to CsA is the down-regulation of various signaling pathways (Granzyme B, ErbB2, NGF, Rho GTPase, AML) that are among others involved in the regulation of cell cycle, apoptosis and extracellular matrix degradation (Mishra et al 2018). Moreover, these pathways are known to be linked to kinases (i.e.…”