Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, Papakostas P, Aravantinos G, Rigakos G, Efstratiou I, Petraki K, Bafaloukos D, Kostopoulos I, et al

Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, Papakostas P, Aravantinos G, Rigakos G, Efstratiou I, Petraki K, Bafaloukos D, Kostopoulos I, et al. a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones. gene is observed in 20%-30% of gastric and gastroesophageal junction GSK6853 cancer [8C12] and is indicative of a poor prognosis, as recently highlighted in the systematic meta-analysis by Jorgensen et al. [13]. In 2010 2010, the phase III ToGA trial showed the superiority of trastuzumab plus chemotherapy (based on a cisplatin-fluoropyrimidine doublet) in patients with HER2-positive metastatic gastric cancer over chemotherapy alone in terms of response rate, progression-free survival (PFS) and overall survival (OS) [14]. These results led to the approval of trastuzumab as the first molecular targeted therapy for gastric cancer. However, subsequent clinical trials (TYTAN8 and LOGiC9) failed to show a survival advantage with the use of another anti-HER2 treatment, lapatinib [15]. Overall, the efficacy of HER2-targeted agents has proven more limited and unsatisfactory than originally expected because the majority of patients with gastric cancer develop acquire resistance to treatment [16]. In particular, it has been observed that, whilst few patients with HER2-positive advanced GSK6853 gastric cancer exhibit primary resistance to trastuzumab, all acquire resistance after a relatively short period of time (median PFS 6.7 months) [17], as already observed in HER2-positive breast cancer patients. The identification of mechanisms underlying treatment resistance would thus enhance the benefit from HER2-targeted therapy in patients with HER2-positive gastric cancer. The etiology of resistance to HER2-directed therapies has been widely investigated in breast cancer [18C22]. Several molecular mechanisms underlying acquired resistance to HER-2 inhibitors have been described, like the activation of Rabbit Polyclonal to IKK-alpha/beta (phospho-Ser176/177) c-Src tyrosine kinase [20], HER3 upregulation [23], activating mutations in the p110a subunit of PI3K (PIK3CA) [24], and improved HER-ligand autocrine signaling [25]. It has additionally shown that level of resistance to HER2-targeted therapy can cause genetic modifications of receptor tyrosine kinases (RTKs), resulting in the activation of downstream signaling goals and choice pathways to pay for HER-2 inhibition [26, 27]. Many studies have figured induction from the HER3 pathway is among the reasons underlying this sort of level of resistance [28C30]. Furthermore, Mohd Nafi et al. noticed that HER4 activation, cleavage and nuclear translocation impact level of resistance and awareness to trastuzumab in HER2-positive breasts cancer tumor [31]. A recent research reported that IQGAP1, a scaffold proteins of 189-kDa portrayed in every individual tissue ubiquitously, governs HER2 appearance, phosphorylation and signaling in breasts cancer tumor cell lines [32]. Furthermore, IQGAP1 protein is normally overexpressed in squamous cell [33] and hepatocellular [34] carcinoma, astrocytoma [35], and intense types of gastric cancers [36]. Specifically, Light et al. [37] demonstrated that IQGAP1overexpression is normally correlated with trastuzumab-induced level of resistance in breasts cancer tumor cell lines. Nevertheless, its participation in level of resistance to trastuzumab in gastric cancers hasn’t been investigated. In today’s work we looked GSK6853 into mechanisms of level of resistance induced by trastuzumab in experimental gastric cancers cell lines rendered resistant to the antiproliferative aftereffect of the medication. RESULTS Baseline appearance and mutational position of HER2, -4 and -3 receptors within a -panel of set up individual gastric cancers cell lines Positivity to HER2, -3 and -4 protein and their mobile localization in the individual gastric cell lines NCI N87, AKG and KKP was evaluated by immunohistochemistry (Amount ?(Figure1A).1A). HER2, -3 and -4 receptors had been portrayed in every 3 cell lines extremely, albeit using a different diffusion design. Specifically, HER2 was extremely portrayed in NCI N87 using a diffuse plasma membrane and cytosolic staining design. HER3 was also extremely portrayed in NCI N87 cells (95% of positive cells) in both plasma membrane and cytosol. Furthermore, HER3 was.