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  • br HER proto oncogene The erbB gene located on the

    2021-09-23


    HER2 proto-oncogene The erbB2 gene, located on the short arm of chromosome 17, was discovered and cloned in 1983 (Fig. 1) (Sato et al., 1983). The product of this gene, HER2, is a transmembrane glycoprotein of 185 KDa that consists of three main domains: an extracellular, a transmembrane and an intracellular domain with tyrosine kinase activity (Cho et al., 2003). The epidermal growth factor Oxaprozin australia family of tyrosine kinases consists of 4 receptor tyrosine kinases (EGFR/erbB1/HER1, erbB2/HER2, erbB3/HER3, and erbB4/HER4) (Cho et al., 2003) that are activated by ligand-induced dimerization (Ushiro & Cohen, 1980). HER2, despite being the only receptor of the family with no known ligand, is the preferred partner for heterodimerization with other erbB members (Graus-Porta, Beerli, Daly, & Oxaprozin australia Hynes, 1997). Receptors dimerization induces transphosphorylation of tyrosine residues within the kinase domains and consequent activation of downstream signaling cascades (Zhang, Gureasko, Shen, Cole, & Kuriyan, 2006; Wagner, Stacey, Liu, & Pawson, 2013). The identification of HER2 amplification/overexpression in a subset of breast cancer and the consequent development of specific anti-HER2 therapies had a tremendous impact on the clinical management of breast cancer patients. In 1998, the US Food and Drug Administration (FDA) approved Trastuzumab, a monoclonal antibody targeting the extracellular domain of HER2, in combination with paclitaxel as first-line treatment in HER2-positive metastatic breast cancer, and as a single agent for second and third-line therapy (Fig. 1). Trastuzumab approval resulted in the inclusion of HER2 testing in the guidelines of the American Society of Clinical Oncology (ASCO) as a recommended test for all breast cancer one year later (Smith et al., 1999). Several studies have shown improvements in progression-free survival (PFS) and overall survival (OS) in HER2-positive breast cancer patients treated with Trastuzumab-based therapies (Vogel, et al., 2002) (Marty et al., 2005). Many other anti HER2 drugs have been further developed and nine are now FDA-approved for breast cancer treatment: Pertuzumab (a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain of the HER2), Ado-trastuzumab Emtansine (TDM-1, a HER2-targeting antibody drug conjugate (ADC)), Neratinib, Lapatinib (a reversible pan-ERBB inhibitor) and five Trastuzumab biosimilars (Fig. 1) (Amiri-Kordestani et al., 2014; Gradishar, 2012; Martin et al., 2017; Blumenthal et al., 2013; Lee et al., 2018; Voelker, 2018). More recently, HER2 amplification/overexpression has also been identified in other tumor types such as gastric, where trastuzumab-based therapy is also standard of care, colon, salivary gland, bladder and uterine serous carcinoma (Buza, English, Santin, & Hui, 2013; Grabsch, Sivakumar, Gray, Gabbert, & Muller, 2010; Bang et al., 2010; Fader et al., 2018).
    Ongoing trials Sixteen clinical trials investigating the efficacy of HER2 targeted therapies in HER2 mutant cancers are currently ongoing (Table 1). Two phase II studies are investigating the efficacy of Neratinib plus Trastuzumab or plus Cetuximab (NCT03457896) and the activity of the ADC DS-8201a (NCT03505710) in non-small lung cancers. Multiple trials investigating the efficacy of Afatinib in HER2 mutant tumors of various histologies are currently enrolling (NCT03810872, NCT02183883, NCT02780687, NCT02597946). In addition, the NCI MATCH trial subprotocol B (NCT02465060) is testing Afatinib in HER2 mutated cancers of any type and is currently enrolling patients nationwide. More trials are investigating the role of Neratinib in combination with other agents such as Fulvestrant (NCT01670877, NCT01953926) in breast cancer or Everolimus, Palbociclib or Trametinib in patients with advanced solid tumors harboring EGFR or HER2 mutation/amplification or HER3/4 mutations (NCT03065387). Additionally, new TKIs are now under clinical investigation: Pyrotinib (an oral irreversible pan-ERBB receptor TKI with activity against HER1, HER2 and HER4) in non-small cell lung cancer and in breast cancer (NCT02834936 and NCT03412383) and Poziotinib (a pan-ERBB inhibitor) in metastatic breast cancer and in patients with advanced NSCLC (NCT02544997, NCT03066206) harboring HER2 mutations.