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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The MAPK signaling pathway (also known as the RAS-RAF-MEK-ERK pathway) is a chain of proteins in cells that communicate a signal from a receptor on the surface of the cell to the DNA in the nucleus. The pathway includes many proteins, including MAPK (Mitogen-Activated Protein Kinases), originally called ERKs (Extracellular signal-Regulated Kinases), which communicate by adding phosphate groups to neighboring proteins (i.e., phosphorylating them), which acts as a series of “on” or “off” switches. The process starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein, producing some change in the cell such as cell division (Figure 6.42). Diagram illustrating the MAPK signaling pathway (Taken from Wikipedia, “MAPK pathway schematic” by Fred the Oyster, under the Creative Commons Attribution-Share Alike 4.0 International license (https://creativecommons.org/licenses/by-sa/4.0/legalcode)).
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
The RAS/RAF/MEK/ERK (or RAS/RAF/mitogen-activated protein kinase, MAPK) signaling cascade is widely activated by a variety of RTKs, including EGFR, and is involved in regulating pleiotropic cellular functions. Extracellular signal-regulated kinase-1 (ERK1) and ERK2A play a major role in the pathway through phosphorylation of downstream mediators involved in cell proliferation, differentiation and survival. A complex network of negative-feedback interactions limits the amplitude and duration of ERK signaling. In a recent study performed on EGFR mutant NSCLC cell models, prolonged erlotinib treatment for 24–48 h produced a rebound in ERK phosphorylation, as was also observed with irreversible EGFR TKIs, afatinib and neratinib (Ma et al., 2016). Phospho-ERK rebound was significantly attenuated by concomitant administration of erlotinib and a MEK inhibitor, trametinib. The MAPK feedback reactivation was further demonstrated to be dependent on MET receptor activation. Interestingly, residual cells after initial erlotinib treatment due to adaptive resistance promoted the development of cell subclones with acquired resistance after long-term treatment with erlotinib, thus suggesting MAPK pathway reactivation triggered by erlotinib may be involved in both mechanisms of resistance and concomitant triggering of EGFR and MAPK could represent a promising therapeutic synergistic approach to inhibit or delay the occurrence of resistance.
Precision medicine for colorectal cancer
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Candan Hızel, Şükrü Tüzmen, Arsalan Amirfallah, Gizem Çalıbaşı Koçal, Duygu Abbasoğlu, Haluk Onat, Yeşim Yıldırım, Yasemin Baskın
Mitogen-activated protein kinase (MAPK) cascades are key signaling pathways involved in the regulation of normal cell proliferation, survival, and differentiation. Dysregulation of MAPK cascades contribute to cancer development. Four distinct MAPK cascades have been identified. They are called extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and ERK5. Each of them is composed of three sequentially acting kinases, activating one after the other (MAPKKK/MAP3K, MAPKK/MAP2K, and MAPK) (Thompson and Lyons, 2005).
Sirtuins as therapeutic targets for improving delayed wound healing in diabetes
Published in Journal of Drug Targeting, 2022
Fathima Beegum, Anuranjana P. V., Krupa Thankam George, Divya K. P., Farmiza Begum, Nandakumar Krishnadas, Rekha R. Shenoy
The role of SIRT 1 in other diabetic complications was also emphasised. Resveratrol was found to be effective in diabetic foot syndrome through SIRT 1 activation and tissue regeneration [105]. It increased the endothelial cell proliferation by activating the ERK signalling pathway and improved cutaneous wound healing [105]. Extracellular signal regulated kinase (ERK) signalling pathway is one of the major signalling cascades of mitogen activated protein kinase signalling pathway. The activation of ERK by SIRT 1 phosphorylates ribosomal S6 kinase (RSK) and ERK translocates to the nucleus where they activate transcription factors including CREB, Fos proto-oncogene (FOS), ETS domain containing protein (Elk-1) eventually resulting in effector protein synthesis causing changes in cell proliferation and survival. CREB, being a cellular transcription factor can enhance gene transcription for above ten times. c-Fos, 380 amino acid protein with basic leucine zipper region for dimerisation and DNA binding and a transactivation domain at C-terminus, is involved in cell proliferation, differentiation and survival. Elk-1 is a protein that is encoded in humans by ELK-1 gene, function as transcription activator. As a result of the activation of SIRT-1, there is enhanced cellular proliferation and improved cutaneous wound healing. The polymer-based sponge loaded with chitosan sodium hyaluronate-resveratrol stimulates tissue regeneration and formation of granulation tissue to facilitate healing of wounds [106].
Involvement of heme oxygenase-1 in suppression of T cell activation by quercetin
Published in Immunopharmacology and Immunotoxicology, 2020
Tomoshi Sugiyama, Miyoko Matsushima, Tomoko Ohdachi, Naozumi Hashimoto, Yoshinori Hasegawa, Kohei Yokoi, Tsutomu Kawabe
Quercetin, concanavalin A (Con A), and A23187 were obtained from Sigma-Aldrich (St. Louis, MO). Anti-CD3ε and anti-CD28 antibodies were obtained from BioLegend Inc. (San Diego, CA). Tin protoporphyrin IX (SnPP) was obtained from Frontier Scientific (Logan, UT). Recombinant murine IL-2 was obtained from Wako Pure Chemical Industries (Osaka, Japan). Antibodies against HO-1 and β-actin were purchased from Assay Designs (Ann Arbor, MI) and MBL (Nagoya, Japan), respectively. Antibodies against extracellular signal-regulated kinase (ERK) 1/2 and against p-ERK1/2 were obtained from Cell Signaling (Boston, MA). Horseradish peroxidase (HRP)-conjugated anti-rabbit IgG and HRP-conjugated anti-mouse IgG and HRP-conjugated anti-rabbit IgG were purchased from Cell Signaling (Boston, MA) and GE Healthcare Bioscience (Buckinghamshire, UK), respectively, for use as secondary antibodies.
Update on BRAF and MEK inhibition for treatment of melanoma in metastatic, unresectable, and adjuvant settings
Published in Expert Opinion on Drug Safety, 2019
Kristy Kummerow Broman, Lesly A Dossett, James Sun, Zeynep Eroglu, Jonathan S Zager
Activating mutations of the MAPK pathway – a regulator of cellular growth and proliferation – are key to the pathogenesis of most cutaneous melanomas [19,20]. MAPK signaling is initiated when extracellular ligands bind to specific membrane-bound receptor tyrosine kinases. Subsequent recruitment and activation of the guanosine triphosphatase RAS (rat sarcoma; encoded by HRAS, NRAS, and KRAS) result in a cascade of phosphorylation events involving the serine/threonine kinase RAF (encoded by ARAF, BRAF and CRAF). Phosphorylation of MAPK kinase (MEK) by RAF activates its only known substrate, ERK (extracellular signal-regulated kinase). Downstream signaling produces oncogenic cell proliferation and escapes from apoptosis [19,20].