Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node

Mutations in the RAS–RAF–MEK–ERK pathway are frequent alterations in cancer and RASopathies, and while RAS oncogene activation alone affects 19% of all patients and accounts for approximately 3.4 million new cases every year, less frequent alterations in the cascade's downstream effectors are a...

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Autores: Scardaci, Rossella, Berlinska, Ewa, Scaparone, Pietro, Vietti Michelina, Sandra, Garbo, Edoardo, Novello, Silvia, Santamaria, David, Ambrogio, Chiara
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/370257
Acceso en línea:http://hdl.handle.net/10261/370257
Access Level:acceso abierto
Palabra clave:Cancer resistance
Inhibitors
Novel therapies
Paradoxical effect
RAF
RAS
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spelling Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF nodeScardaci, RossellaBerlinska, EwaScaparone, PietroVietti Michelina, SandraGarbo, EdoardoNovello, SilviaSantamaria, DavidAmbrogio, ChiaraCancer resistanceInhibitorsNovel therapiesParadoxical effectRAFRASMutations in the RAS–RAF–MEK–ERK pathway are frequent alterations in cancer and RASopathies, and while RAS oncogene activation alone affects 19% of all patients and accounts for approximately 3.4 million new cases every year, less frequent alterations in the cascade's downstream effectors are also involved in cancer etiology. RAS proteins initiate the signaling cascade by promoting the dimerization of RAF kinases, which can act as oncoproteins as well: BRAFV600E is the most common oncogenic driver, mutated in the 8% of all malignancies. Research in this field led to the development of drugs that target the BRAFV600-like mutations (Class I), which are now utilized in clinics, but cause paradoxical activation of the pathway and resistance development. Furthermore, they are ineffective against non-BRAFV600E malignancies that dimerize and could be either RTK/RAS independent or dependent (Class II and III, respectively), which are still lacking an effective treatment. This review discusses the recent advances in anti-RAF therapies, including paradox breakers, dimer-inhibitors, immunotherapies, and other novel approaches, critically evaluating their efficacy in overcoming the therapeutic limitations, and their putative role in blocking the RAS pathway.Giovanni Armenise–Harvard Foundation European Research Council (ERC). Grant Number: 101001288 Associazione Italiana per la Ricerca sul Cancro. Grant Number: 25737Peer reviewedJohn Wiley & SonsGiovanni Armenise Harvard FoundationEuropean Research CouncilEuropean CommissionAssociazione Italiana per la Ricerca sul CancroConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_dcae04bcPublisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/370257reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/EC/H2020/101001288The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1002/1878-0261.13605https://doi.org/10.1002/1878-0261.13605Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3702572026-05-22T06:33:51Z
dc.title.none.fl_str_mv Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node
title Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node
spellingShingle Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node
Scardaci, Rossella
Cancer resistance
Inhibitors
Novel therapies
Paradoxical effect
RAF
RAS
title_short Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node
title_full Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node
title_fullStr Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node
title_full_unstemmed Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node
title_sort Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node
dc.creator.none.fl_str_mv Scardaci, Rossella
Berlinska, Ewa
Scaparone, Pietro
Vietti Michelina, Sandra
Garbo, Edoardo
Novello, Silvia
Santamaria, David
Ambrogio, Chiara
author Scardaci, Rossella
author_facet Scardaci, Rossella
Berlinska, Ewa
Scaparone, Pietro
Vietti Michelina, Sandra
Garbo, Edoardo
Novello, Silvia
Santamaria, David
Ambrogio, Chiara
author_role author
author2 Berlinska, Ewa
Scaparone, Pietro
Vietti Michelina, Sandra
Garbo, Edoardo
Novello, Silvia
Santamaria, David
Ambrogio, Chiara
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Giovanni Armenise Harvard Foundation
European Research Council
European Commission
Associazione Italiana per la Ricerca sul Cancro
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cancer resistance
Inhibitors
Novel therapies
Paradoxical effect
RAF
RAS
topic Cancer resistance
Inhibitors
Novel therapies
Paradoxical effect
RAF
RAS
description Mutations in the RAS–RAF–MEK–ERK pathway are frequent alterations in cancer and RASopathies, and while RAS oncogene activation alone affects 19% of all patients and accounts for approximately 3.4 million new cases every year, less frequent alterations in the cascade's downstream effectors are also involved in cancer etiology. RAS proteins initiate the signaling cascade by promoting the dimerization of RAF kinases, which can act as oncoproteins as well: BRAFV600E is the most common oncogenic driver, mutated in the 8% of all malignancies. Research in this field led to the development of drugs that target the BRAFV600-like mutations (Class I), which are now utilized in clinics, but cause paradoxical activation of the pathway and resistance development. Furthermore, they are ineffective against non-BRAFV600E malignancies that dimerize and could be either RTK/RAS independent or dependent (Class II and III, respectively), which are still lacking an effective treatment. This review discusses the recent advances in anti-RAF therapies, including paradox breakers, dimer-inhibitors, immunotherapies, and other novel approaches, critically evaluating their efficacy in overcoming the therapeutic limitations, and their putative role in blocking the RAS pathway.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_dcae04bc
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/370257
url http://hdl.handle.net/10261/370257
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/EC/H2020/101001288
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1002/1878-0261.13605
https://doi.org/10.1002/1878-0261.13605
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv John Wiley & Sons
publisher.none.fl_str_mv John Wiley & Sons
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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