Genetics in Otology and Neurotology
John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie in Basic Sciences Endocrine Surgery Rhinology, 2018
The loss of Merlin protein in NF2 has been shown to result in abnormal activation of the epidermal growth factor receptor (EGFR) receptor tyrosine kinases (RTKs) proteins. The proteins implicated include EGFR, ErbB2 and ErbB3. These proteins all span the cell membrane and contribute to feedback loops that regulate both cell death and cell division. When Merlin is inactive, EGFR, ErbB2 and ErbB3 remain constitutively active allowing increased cell proliferation and resistance to cell death.57 Lapatinib is an oral dual EGFR/ErbB2 inhibitor approved for use in breast cancer. In preclinical studies lapatinib was shown to have substantial inhibition of both cell proliferation and vestibular schwannomas growth.58, 59 Lapatinib is now being investigated in two ongoing clinical studies in patients with NF2.
Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
HER-2 is a member of the Human epidermal growth factor receptor (HER) family of transmembrane receptor tyrosine kinases. Other members of this family include HER1 (epidermal growth factor receptor [EGFR]), HER3 (erbB3), and HER4 (erbB4). HER2 is constitutively active and has no ligand. Overexpression, gene amplification or mutation of HER-2 affects the downstream PI3K-Akt and MAPK pathways, leading to the disruption of the regulation of cell-cycle progression and apoptosis [80, 81]. Approximately 2-4% of NSCLC have HER2 mutations, which seem to be mutually exclusive from EGFR/KRAS/ALK-mutations. HER-2 gene amplification and HER-2 over expression are more prevalent (20% and 35% of NSCLC cases) [82]. HER-2 overexpression [by immunohistochemistry (IHC)] was found to be a marker for poor prognosis in NSCLC (HR 1.48; 95% CI: 1.22–1.80) in a meta-analysis of 6135 patients [83].
Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
ErbB-1 (EGFR) and ErbB-2 are receptor kinase targets over-expressed in a number of tumor types, including breast, lung, pancreas, colon, and head and neck cancers. Varlitinib (Figure 6.21) was identified by Aslan Pharmaceuticals as a novel orally available ErbB family inhibitor that, unlike other approved ErbB inhibitors at the time, targeted all members of the ErbB family including ErbB3, either directly or indirectly, and thus had potential advantages in treating tumors that signal through multiple ErbB pathways. In preclinical studies it was shown to be a potent reversible inhibitor of EGFR, HER2, and HER4, and was active as both a single agent and in combination with trastuzumab (HerceptinTM), capecitabine (XelodaTM), and docetaxel (TaxotereTM) in tumor models signaling through multiple ErbB pathways. Structure of varlitinib (ASLAN001, ARRY-543).
Current and future therapies for targeting HER2 mutations in gastrointestinal cancer
Published in Expert Review of Anticancer Therapy, 2018
Recent evidence suggests that ERBB3 (HER3) serves as a key activator of downstream signaling through dimerization with other ERBB proteins and plays a critical role in the widespread clinical resistance to EGFR and HER2 targeting cancer therapies. In contrast to HER2, HER3 can bind multiple ligands but it lacks a functioning kinase domain and is, therefore, unable to homodimerize and to induce downstream signaling pathway activation on its own. However, in the presence of HER3 ligands, HER3may promote the kinase activity of EGFR or HER2 and thereby induce phosphorylation of the HER3 C-terminal tail inducing the PI3K/Akt pathway activation by creating heterodimers [28]. HER2 is the preferred dimerization partner and the HER2–HER3 dimer seems to be the most potent HER family dimer, contributing to anti-HER2 therapy resistance [29]. As a result, considerable efforts are pursued on developing new therapies that target HER3.
HER2 overexpression is a putative diagnostic and prognostic biomarker for late-stage colorectal cancer in North African patients
Published in Libyan Journal of Medicine, 2021
Eman A. Abdul Razzaq, Thenmozhi Venkatachalam, Khuloud Bajbouj, Mohamed Rahmani, Amena Mahdami, Surendra Rawat, Naziha Mansuri, Hussein Alhashemi, Rifat Akram Hamoudi, Riyad Bendardaf
Moreover, alterations in the HER2 dimerization partner HER3, encoded by the ERBB3 gene, also affects HER2 signaling and the sensitivity to targeted therapies. Namely, the first anti‐HER2 targeting antibody, trastuzumab, used since 1998, binds the extracellular domain of HER2 transmembrane receptor, crucial for its dimerization, in selected patients based on their immunohistochemical and PCR profile [9]. Another drug targeting the dimerization domain, at a different binding site than trastuzumab, is pertuzumab, which is still a recombinant humanized anti-HER2 IgG1 monoclonal antibody. Its effectiveness is rather low when used alone, but the combination of both trastuzumab and pertuzumab has been shown to act synergistically both in vitro and in vivo in inhibiting tumor growth, at least for breast cancer. Phase II clinical trials, such as CLEOPATRA and APHINITY study have shown prolonged overall survival and disease free survival Similar studies are now under way for colorectal cancer. Another line of treatment involves the Lapatinib, an intracellular blocker approved for both HER2 and EGFR receptors simultaneously, which shows much greater overall inhibitory effects [6].
New insights into ErbB3 function and therapeutic targeting in cancer
Published in Expert Review of Anticancer Therapy, 2020
Umbreen Hafeez, Adam C Parslow, Hui K Gan, Andrew M Scott
ErbB3, a member of the EGFR family of receptor tyrosine kinases is an important therapeutic target in cancer. As outlined in this review, ErbB3 plays a significant role in carcinogenesis by activating various downstream signaling pathways. Cancer cells harboring ErbB3 mutations or overexpression can proliferate, inhibit apoptosis, evade the immune system, and metastasize. ErbB3 overexpression and less commonly ErbB3 mutations are related to a worse prognosis. Recent data on the problem of drug resistance has demonstrated that inactivation of ErbB3 downstream signaling is required to overcome primary or acquired drug resistance to various targeted therapies and chemotherapeutic agents. Currently, there is no approved anti-ErbB3 therapy in clinical practice. However, a large number of experimental drugs in the pipeline targeting ErbB3 and its partners promise that ErbB3 targeting will gain momentum, and effective therapies will be available for patients in the future.
Related Knowledge Centers
- Allosteric Regulation
- ERBB
- Ligand
- Neuregulin 1
- Protein
- Gene
- Her2
- Neuregulin 2
- Pi3K/Akt/Mtor Pathway
- Phosphoinositide 3-Kinase