China
Africa
Explore chapters and articles related to this topic
Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
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
Published in David E. Thurston, Ilona Pysz, 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).
Adaptive Resistance Mechanisms in EGFR Mutant NSCLC
Published in Il-Jin Kim, Companion Diagnostics (CDx) in Precision Medicine, 2019
Mariacarmela Santarpia, Niki Karachaliou, Martyna Filipska, Clara Mayo-de-las-Casas, Chiara Lazzari, Maria González-Cao, Rafael Rosell
In EGFR and HER2-driven cancer models, MEK inhibition induced activation of PI3K/AKT through hyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane domains of EGFR and HER2 (Turke et al., 2012). Indeed, direct ERK-mediated phosphorylation of EGFR T669 and HER2 T677 suppresses activation of ERBB3. These findings suggest that combining MEK inhibition with ERBB3 or PI3K inhibitors may be a valuable strategy in these oncogene-addicted cancer cells.
NRG1 and NRG2 fusions in non-small cell lung cancer (NSCLC): seven years between lights and shadows
Published in Expert Opinion on Therapeutic Targets, 2021
Domenico Trombetta, Angelo Sparaneo, Federico Pio Fabrizio, Concetta Martina Di Micco, Antonio Rossi, Lucia Anna Muscarella
Similar to other gene fusions, the transversal occurrence of the NRG1 fusions in different tumor histologies, locations and clinical context indicate that it represents a master molecular alteration to include in the panel of targetable genes and that blocking the activity of NRG1-ErbB-PI3K-AKT pathway might be the best strategy to treat tumors having NRG1 fusions. However, due to the low incidence and poor knowledge about the biological consequences of the different NRG1 and NRG2 fusions, the potential activity of a variety of cytotoxic, immune, and targeted therapies against these cancers remains disappointing so far. There is increasing evidence on the therapeutic efficacy of ErbB2/ErbB3 targeting in these tumors and many trials are still ongoing or planned to evaluate this approach in the clinic.
An updated patent review of Akt inhibitors (2016-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Yu Guo, Yizhen Jin, Bingxue Qu, Yu Zhang, Jinxin Che, Xiaowu Dong
As mentioned above, Akt, a protein kinase that plays an essential role in cancer, is associated with various proteins and receptors in tumor cell survival, proliferation, and apoptosis pathways [56]. Therefore, anti-tumor strategies of Akt inhibitors combined with other pathway regulators have been widely publicized since 2016 (Figure 8). Phosphatidylinositol 3-kinase (PI3K), an intracellular phosphatidylinositol kinase, can activate PDK1 through phosphorylation to further phosphorylate Akt at threonine 308, resulting in Akt activation. PI3K is widely considered to be the upstream protein of Akt [57]. Therefore, Giordano disclosed a method combining the selective PI3K inhibitor BYL719 with Akt allosteric inhibitor MK2206 to treat solid tumors [58]. The extracellular activation signal of PI3K can be derived from various growth factors and signaling complexes that can generally interact with receptor tyrosine kinase (RTK) to cause the autophosphorylation of RTK [59]. So, as the upstream of PI3K signal, the combined strategy of inhibiting RTK and Akt is also logical. HER3 (erbB3), a member of the epidermal growth factor receptor (EGFR) family, is an overexpressed RTK in various cancers. Therefore, the strategy published by Zhang et al. in 2018 to combine PI3K/Akt pathway inhibitors with erbB3 monoclonal antibody has become very significant [60]. A bi-specific anti-erbB2/anti-erbB3 antibody (MM-111) is also described in the patent [60].
In vitro study of the effects of DC electric fields on cell activities and gene expression in human choriocarcinoma cells
Published in Electromagnetic Biology and Medicine, 2021
Jinxin Chen, Linbo Guan, Ping Fan, Xinghui Liu, Rui Liu, Yu Liu, Huai Bai
ErbB belongs to the human epidermal growth factor receptor (HER) family of transmembrane tyrosine kinases, including ErbB1(EGFR), ErbB2, ErbB3, and ErbB4 (Sirica 2008). Upon ligand binding, ErbB homodimers or heterodimers are activated by autophosphorylation and then combine with some intermediate proteins, which elicit several downstream cascades and lead to important biological effects, including cell movement, proliferation, adhesion, and differentiation (Linggi and Carpenter 2006; Sirica 2008). Our results showed that the expression of EGFR, ErbB4, Crk (CrkL), CDKN1A (P21), and JUN genes was upregulated in the ErbB signaling pathway in choriocarcinoma cells stimulated by DC EF. Several studies have shown that the overexpression or overactivity of EGFR is associated with enhanced migration or proliferation of several types of cells, including keratinocytes and myofibroblasts (Andl et al. 2003; Zuo et al. 2018).