Targeting KRAS mutant lung cancer: light at the end of the tunnel.

For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRASG12...

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Detalles Bibliográficos
Autores: Drosten, Matthias, Barbacid, Mariano
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/14702
Acceso en línea:http://hdl.handle.net/20.500.12105/14702
Access Level:acceso abierto
Palabra clave:Adenocarcinoma of Lung
Lung Neoplasms
Humans
Mutation
Oncogenes
Protein Kinase Inhibitors
Proto-Oncogene Proteins p21(ras)
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spelling Targeting KRAS mutant lung cancer: light at the end of the tunnel.Drosten, MatthiasBarbacid, MarianoAdenocarcinoma of LungLung NeoplasmsHumansMutationOncogenesProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRASG12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen-activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.WileyUnión Europea. Comisión Europea. European Research Council (ERC)Government of SpainUnión Europea. Comisión EuropeaComunidad de Madrid (España)CRIS contra el CáncerFundación AXA20222022-07-1320222022-05-1620222022-05-16journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/14702reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 695566open accesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial-CompartirIgual 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/147022026-06-12T12:43:37Z
dc.title.none.fl_str_mv Targeting KRAS mutant lung cancer: light at the end of the tunnel.
title Targeting KRAS mutant lung cancer: light at the end of the tunnel.
spellingShingle Targeting KRAS mutant lung cancer: light at the end of the tunnel.
Drosten, Matthias
Adenocarcinoma of Lung
Lung Neoplasms
Humans
Mutation
Oncogenes
Protein Kinase Inhibitors
Proto-Oncogene Proteins p21(ras)
title_short Targeting KRAS mutant lung cancer: light at the end of the tunnel.
title_full Targeting KRAS mutant lung cancer: light at the end of the tunnel.
title_fullStr Targeting KRAS mutant lung cancer: light at the end of the tunnel.
title_full_unstemmed Targeting KRAS mutant lung cancer: light at the end of the tunnel.
title_sort Targeting KRAS mutant lung cancer: light at the end of the tunnel.
dc.creator.none.fl_str_mv Drosten, Matthias
Barbacid, Mariano
author Drosten, Matthias
author_facet Drosten, Matthias
Barbacid, Mariano
author_role author
author2 Barbacid, Mariano
author2_role author
dc.contributor.none.fl_str_mv Unión Europea. Comisión Europea. European Research Council (ERC)
Government of Spain
Unión Europea. Comisión Europea
Comunidad de Madrid (España)
CRIS contra el Cáncer
Fundación AXA
dc.subject.none.fl_str_mv Adenocarcinoma of Lung
Lung Neoplasms
Humans
Mutation
Oncogenes
Protein Kinase Inhibitors
Proto-Oncogene Proteins p21(ras)
topic Adenocarcinoma of Lung
Lung Neoplasms
Humans
Mutation
Oncogenes
Protein Kinase Inhibitors
Proto-Oncogene Proteins p21(ras)
description For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRASG12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen-activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-07-13
2022
2022-05-16
2022
2022-05-16
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/14702
url http://hdl.handle.net/20.500.12105/14702
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 695566
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 4.0 Internacional
http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 4.0 Internacional
http://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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