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dc.contributor.authorArozarena, I
dc.contributor.authorWellbrock, Claudia
dc.date.accessioned2017-12-15T15:29:22Z
dc.date.available2017-12-15T15:29:22Z
dc.date.issued2017-10
dc.identifier.citationOvercoming resistance to BRAF inhibitors. 2017, 5 (19):387 Ann Transl Meden
dc.identifier.issn2305-5839
dc.identifier.pmid29114545
dc.identifier.doi10.21037/atm.2017.06.09
dc.identifier.urihttp://hdl.handle.net/10541/620730
dc.description.abstractThe discovery of activating mutations in the serine/threonine (S/T) kinase BRAF followed by a wave of follow-up research manifested that the MAPK-pathway plays a critical role in melanoma initiation and progression. BRAF and MEK inhibitors produce an unparalleled response rate in melanoma, but it is now clear that most responses are transient, and while some patients show long lasting responses the majority progress within 1 year. In accordance with the key role played by the MAPK-pathway in BRAF mutant melanomas, disease progression is mostly due to the appearance of drug-resistance mechanisms leading to restoration of MAPK-pathway activity. In the present article we will review the development, application and clinical effects of BRAF and MEK inhibitors both, as single agent and in combination in the context of targeted therapy in melanoma. We will then describe the most prominent mechanisms of resistance found in patients progressed on these targeted therapies. Finally we will discuss strategies for further optimizing the use of MAPK inhibitors and will describe the potential of alternative combination therapies to either delay the onset of resistance to MAPK inhibitors or directly target specific mechanisms of resistance to BRAF/MEK inhibitors.
dc.language.isoenen
dc.rightsArchived with thanks to Annals of translational medicineen
dc.titleOvercoming resistance to BRAF inhibitors.en
dc.typeArticleen
dc.contributor.departmentNavarrabiomed-Fundacion Miguel Servet-Idisna, Complejo Hospitalario de Navarra, Pamplona, Spainen
dc.identifier.journalAnnals of Translational Medicineen
html.description.abstractThe discovery of activating mutations in the serine/threonine (S/T) kinase BRAF followed by a wave of follow-up research manifested that the MAPK-pathway plays a critical role in melanoma initiation and progression. BRAF and MEK inhibitors produce an unparalleled response rate in melanoma, but it is now clear that most responses are transient, and while some patients show long lasting responses the majority progress within 1 year. In accordance with the key role played by the MAPK-pathway in BRAF mutant melanomas, disease progression is mostly due to the appearance of drug-resistance mechanisms leading to restoration of MAPK-pathway activity. In the present article we will review the development, application and clinical effects of BRAF and MEK inhibitors both, as single agent and in combination in the context of targeted therapy in melanoma. We will then describe the most prominent mechanisms of resistance found in patients progressed on these targeted therapies. Finally we will discuss strategies for further optimizing the use of MAPK inhibitors and will describe the potential of alternative combination therapies to either delay the onset of resistance to MAPK inhibitors or directly target specific mechanisms of resistance to BRAF/MEK inhibitors.


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