Understanding the biology of HER3 receptor as a therapeutic target in human cancer

Abstract

HER3 belongs to the human epidermal growth factor receptor (HER) family which also includes HER1/EGFR/erbB1, HER2/erbB2, and HER4/erbB4. As a unique member of the HER family, HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases (RTKs) in cancer cells to activate oncogenic signaling, especially the PI-3K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors. Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients.

Retracted Article: MiR-148a agomir based targeting of c-Met and Her-3 is able to attenuate EGFR-T790M mutation driven gefitinib and erlotinib resistance in non-small cell lung cancer cells

“…Activation of c-Met upon ligation with its ligand hepatocyte growth factor bypasses EGFR inhibition by activating the JAK-STAT3, PI3K-Akt-mTOR and MAPK pathways, 23,24 while Her-3 might activate c-Met or EGFR without ligand binding by dimerizing with these growth factor receptors. 13,25 Moreover, previous study suggested that the coexistence of Met ad T790M mutation contributed to EGFR TKI resistance in advanced NSCLC. 26 These works indicated c-Met and Her-3 might serve as possible therapeutic target for the treatment of EGFR TKI resistant, metastatic or advanced-stage NSCLC.…”

“…Previous researches have demonstrated that miR-148a would suppress the gene expression of ERBB3, 10 MET 11 and IGF1R 12 via directly interacting with the target sequences on the 3 0 untranslated regions (3 0 UTRs) of these genes' mRNAs, thus triggering gene silencing mediated by the RNA-induced silencing complex (RISC). Her-3, Insulin growth factor-1 receptor and c-Met proteins are three growth factor receptors encoded by these three genes, whose upregulation plays pivotal role in the development of EGFR TKI resistance in NSCLC, [13][14][15] and targeting these proteins has been suggested to improve the therapeutic effect of EGFR TKI against NSCLC. [16][17][18][19] The present research attempted to explore whether and how miR-148a would regulate NSCLC cells' resistance to EGFR TKI treatment.…”

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

“…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.…”

Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells

“…Second, P2Y12 could regulate EGFR activation by promoting EGFR association with another member of the EGFR family, the human epidermal growth factor receptor 3 (HER3). Thus, inhibition of the purinergic receptor could reduce HER3 activation, and subsequently EGFR activation [19,43]. Third, P2Y12 could induce EGFR activation via Src, then the transactivated EGFR forms a multireceptor complex with P2Y12, leading to an increase in the downstream oncogenic signaling [44].…”