Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors
Abstract Searching for targets that allow pharmacological inhibition of cell proliferation in over-proliferative states, such as cancer, leads us to finely understand the complex mechanisms orchestrating the perfect control of mitosis number, frequency and pace as well as the molecular arrangements...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Molecular Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12943-018-0792-2 |
| _version_ | 1811264667138392064 |
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| author | Wagner Ricardo Montor Andrei Ronaldo Oliveira Silva Escartin Salas Fabiana Henriques Machado de Melo |
| author_facet | Wagner Ricardo Montor Andrei Ronaldo Oliveira Silva Escartin Salas Fabiana Henriques Machado de Melo |
| author_sort | Wagner Ricardo Montor |
| collection | DOAJ |
| description | Abstract Searching for targets that allow pharmacological inhibition of cell proliferation in over-proliferative states, such as cancer, leads us to finely understand the complex mechanisms orchestrating the perfect control of mitosis number, frequency and pace as well as the molecular arrangements that induce cells to enter functional quiescence and brings them back to cycling in specific conditions. Although the mechanisms regulating cell proliferation have been described several years ago, never before has so much light been shed over this machinery as during the last decade when therapy targets have been explored and molecules, either synthetic or in the form of antibodies with the potential of becoming cancer drugs were produced and adjusted for specific binding and function. Proteins containing tyrosine kinase domains, either membrane receptors or cytoplasmic molecules, plus the ones activated by those in downstream pathways, having tyrosine kinase domains or not, such as RAS which is a GTPase and serine/threonine kinases such as RAF, play crucial role in conducting proliferation information from cell surroundings to the nucleus where gene expression takes place. Tyrosine kinases phosphorylate tyrosine residues in an activating mode and are found in important growth factor receptors, such as for ligands from families collectively known as VEGF, PDGF and EGF, to name a few and in intracellular downstream molecules. They all play important roles in normal physiology and are commonly found mutated or overexpressed in neoplastic states. Our objective here is to present such kinases as druggable targets for cancer therapy, highlighting the ones for which the pharmacological arsenal is available, discussing specificity, resistance mechanisms and treatment alternatives in cases of resistance, plus listing potential targets that have not been successfully worked yet. |
| first_indexed | 2024-04-12T20:07:22Z |
| format | Article |
| id | doaj.art-d17a0c0ac06f41b694fca5eeb5aca4e5 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-04-12T20:07:22Z |
| publishDate | 2018-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-d17a0c0ac06f41b694fca5eeb5aca4e52022-12-22T03:18:21ZengBMCMolecular Cancer1476-45982018-02-0117111810.1186/s12943-018-0792-2Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitorsWagner Ricardo Montor0Andrei Ronaldo Oliveira Silva Escartin Salas1Fabiana Henriques Machado de Melo2Departamento de Ciências Fisiológicas, Faculdade de Ciências Médicas da Santa Casa de São PauloDepartamento de Ciências Fisiológicas, Faculdade de Ciências Médicas da Santa Casa de São PauloDepartamento de Ciências Fisiológicas, Faculdade de Ciências Médicas da Santa Casa de São PauloAbstract Searching for targets that allow pharmacological inhibition of cell proliferation in over-proliferative states, such as cancer, leads us to finely understand the complex mechanisms orchestrating the perfect control of mitosis number, frequency and pace as well as the molecular arrangements that induce cells to enter functional quiescence and brings them back to cycling in specific conditions. Although the mechanisms regulating cell proliferation have been described several years ago, never before has so much light been shed over this machinery as during the last decade when therapy targets have been explored and molecules, either synthetic or in the form of antibodies with the potential of becoming cancer drugs were produced and adjusted for specific binding and function. Proteins containing tyrosine kinase domains, either membrane receptors or cytoplasmic molecules, plus the ones activated by those in downstream pathways, having tyrosine kinase domains or not, such as RAS which is a GTPase and serine/threonine kinases such as RAF, play crucial role in conducting proliferation information from cell surroundings to the nucleus where gene expression takes place. Tyrosine kinases phosphorylate tyrosine residues in an activating mode and are found in important growth factor receptors, such as for ligands from families collectively known as VEGF, PDGF and EGF, to name a few and in intracellular downstream molecules. They all play important roles in normal physiology and are commonly found mutated or overexpressed in neoplastic states. Our objective here is to present such kinases as druggable targets for cancer therapy, highlighting the ones for which the pharmacological arsenal is available, discussing specificity, resistance mechanisms and treatment alternatives in cases of resistance, plus listing potential targets that have not been successfully worked yet.http://link.springer.com/article/10.1186/s12943-018-0792-2Receptor tyrosine kinasestyrosine kinase inhibitorsMAPK signaling pathwaysRAS-mutationsBRAF driven cancersPI3K/AKT transduction network |
| spellingShingle | Wagner Ricardo Montor Andrei Ronaldo Oliveira Silva Escartin Salas Fabiana Henriques Machado de Melo Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors Molecular Cancer Receptor tyrosine kinases tyrosine kinase inhibitors MAPK signaling pathways RAS-mutations BRAF driven cancers PI3K/AKT transduction network |
| title | Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors |
| title_full | Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors |
| title_fullStr | Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors |
| title_full_unstemmed | Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors |
| title_short | Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors |
| title_sort | receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment the current arsenal of inhibitors |
| topic | Receptor tyrosine kinases tyrosine kinase inhibitors MAPK signaling pathways RAS-mutations BRAF driven cancers PI3K/AKT transduction network |
| url | http://link.springer.com/article/10.1186/s12943-018-0792-2 |
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