Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial-mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited β-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.
Lung carcinoma is the leading cause of carcinoma death in the world. Despite recent advances in understanding the molecular biology of lung cancer and the introduction of new therapeutic agents for its treatment, its dismal 5-year survival rate has not changed substantially. Clinical approaches have not significantly improved the survival of patients with advanced lung cancer. However, recent discoveries about the molecular mechanisms responsible for lung cancer initiation and proliferation have unveiled new targets for therapy. One of the hallmark features of cancer cells is their ability to evade programmed cell death or apoptosis. Alterations in pro- and anti-apoptotic pathways are common in cancer cells and defects in regulation of apoptosis have been implicated in both lung tumorigenesis and drug resistance. Thus, targeting apoptosis through the direct or indirect manipulation of the pro-apoptotic machinery offers a novel strategy for treatment. This mini review summaries the molecular events that contribute to drug-induced apoptosis and how lung tumors evade apoptotic death followed by an analysis of the implications for treatment.
Although there was no statistically significant difference between patients treated with or without a transparent cap, hemoclipping with the aid of the cap made it possible to clip a lesion too tangential to be clipped without it. However, this study did not compare conventional hemoclipping with hemoclipping using a cap because the cap was only used in cases in which conventional clipping had failed.
Phenylethanolamine N-methyltransferase (PNMT)-like immunoreactivity has been found in psoriatic skin and in this study, PNMT-like immunoreactivity was investigated in the involved and uninvolved skin of six patients with lichen planus and four patients with lichen simplex. No PNMT immunoreactivity was observed in these diseases. Studies were carried out using cultured fibroblasts from two patients with psoriasis from uninvolved and involved areas of skin and from two controls using antibodies to PNMT, as well as antibodies to the chemical messengers somatostatin, substance P, parathyroid hormone and peptide histidine isoleucine amide. No immunoreactivity to these substances was found, and fibroblasts are unlikely to be the cellular origin of the PNMT-like immunoreactivity as seen in psoriatic skin.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.