Small Molecule Tyrosine Kinase Inhibitors of ErbB2/HER2/Neu in the Treatment of Aggressive Breast Cancer

Abstract

Abstract:The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin ® ) and lapatinib (Tyverb/Tykerb ® ), a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, respectively, are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed.

In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

“…S1 and Dataset S1), further confirming that these genes are essential for PC tumors to survive. Among the top 10 genes, ERBB2 and RAF1 are well-known oncogenes in many solid tumors (13,14) and several HER2 inhibitors have already been used in the clinic for multiple cancer types (15), confirming that our screen is capable of identifying promising drug targets.…”

Recent Progress in HER2 Associated Breast Cancer

“…The HER2 oncogene is located on the long arm of chromosome 17 (17q12), consisting of EGFR (HER1/ ERBB1), HER3 (ERBB3), and HER4 (ERBB4) (Arcila et al, 2012;Kanthala et al, 2014;Kurata et al, 2014;Schroeder et al, 2014;Xu et al, 2014;Yan et al, 2014), it is a receptor tyrosine kinase (Morrison et al, 2014;Schroeder et al, 2014), once activated, by ways homodimerization or hetero-dimerization (Boulbes et al,Seen from many previous studies, HER2 overexpression has been linked to more aggressive disease and poorer prognosis in node-positive breast cancer. In patients with HER2-over-expressing tumors, different researches have shown cellular and/or humoral immune responses against HER2 associated with a lower tumor development at early stages of the disease (Ladjemi et al, 2010;Xia et al, 2013;Lanning et al, 2015).…”

“…Joyfully, about the mutant mechanism, researchers newly reported a case that a breast cancer patient harboring an activating EGFR mutation clinically benefiting from EGFR-targeted treatment (Ali et al, 2014). The immune way ADCC (Nahta, 2012) multiple mAbs HER2 internalization (Ben-Kasu et al, 2009) anti-HER2 vaccine Peptide-based/DNA-based/ anti-idiotypic (Cao et al, 2013;Tagliabue and Campiglio, 2014) Trastuzumab mitogenic signaling (Schroeder et al, 2014;Kawajiri et al, 2015) ADCC 188Re-labeled HYNIC-trastuzuma radioactivity dose-dependent fashion (Luo et al, 2015) 64Cu-DOTA-trastuzumab metastatic breast cancer (Mortimer et al, 2014) Trastuzumab resistance Upregulation of HER3 (Nahta, 2012;Brady et al, 2014;Rimawi et al, 2014;Zang et al, 2014;Nam et al, 2015) miRNAs (miRNA-21, miR-7, miR-200c) (Bai et al, 2014;Chen and Bourguignon, 2014;Huynh and Jones, 2014; H E R 2 c o p y n u m b e r / dimerization status Interaction between HER2 and other ERBB (Lee et al, 2015) autophagy (Yeh et al, 2014) Anthracyclines HER2/TOP2A (Fountzilas et al, 2012) S-222611 ERBB family dimmers (Spicer et al, 2015) NCT Increase pCR rates (Shinde et al, 2015) Flotillin reduction of ErbB2-ErbB3 (Asp and Pust, 2014) CC apoptosis/ proliferation (Khan et al, 2015) Taspase1 Cyclins E, A, and B (Dong et al, 2014) Combined therapy Trastuzumab, carboplatin, paclitaxel (Shinde et al, 2015) Trastuzumab, MK-2206 (Hudis et al, 2013) Trastuzumab, lapatinib (Rimawi et al, 2014;Scaltriti et al, 2014;Schroeder et al, 2014) lapatinib , BYL719 (Brady et al, 2014) AZD8931, paclitaxel (Kurata et al, 2014) Hsp90, laptinib ( …”

Identifying Differentially Expressed Genes and Screening Small Molecule Drugs for Lapatinib-resistance of Breast Cancer by a Bioinformatics Strategy

“…Over-expression of human epidermal growth factor receptor 2 (HER2) occurs in nearly 15%-30% of breast cancers, and is associated with increased disease recurrence, nodal metastasis and worse prognosis (Ba et al, 2014;Schroeder et al, 2014). Use of Lapatinib, an orally active dual EGFR/HER2 tyrosine kinase inhibitor, showed significant improvement in the outcomes of patients with HER2-positive breast cancer, including progression free survival (PFS) and overall survival (OS) (Kacan et al, 2014).…”