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KSR induces RAS-independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors.

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dc.contributor.authorPaniagua, Guillen
dc.contributor.authorJacob, Harrys K C
dc.contributor.authorBrehey, Oksana
dc.contributor.authorGarcía-Alonso, Sara
dc.contributor.authorPons, Tirso
dc.contributor.authorMusteanu, Mónica
dc.contributor.authorDrosten, Matthias
dc.contributor.authorGuerra, Carmen
dc.contributor.authorBarbacid, Mariano
dc.contributor.authorLechuga, Carmen G
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC)es_ES
dc.contributor.funderGovernment of Spaines_ES
dc.contributor.funderComunidad de Madrid (España)es_ES
dc.contributor.funderCRIS contra el Cánceres_ES
dc.date.accessioned2022-07-13T08:57:24Z
dc.date.available2022-07-13T08:57:24Z
dc.date.issued2022-03-21
dc.description.abstractThe kinase suppressor of rat sarcoma (RAS) proteins (KSR1 and KSR2) have long been considered as scaffolding proteins required for optimal mitogen-activated protein kinase (MAPK) pathway signalling. However, recent evidence suggests that they play a more complex role within this pathway. Here, we demonstrate that ectopic expression of KSR1 or KSR2 is sufficient to activate the MAPK pathway and to induce cell proliferation in the absence of RAS proteins. In contrast, the ectopic expression of KSR proteins is not sufficient to induce cell proliferation in the absence of either rapidly accelerated fibrosarcoma (RAF) or MAPK-ERK kinase proteins, indicating that they act upstream of RAF. Indeed, KSR1 requires dimerization with at least one member of the RAF family to stimulate proliferation, an event that results in the translocation of the heterodimerized RAF protein to the cell membrane. Mutations in the conserved aspartic acid-phenylalanine-glycine motif of KSR1 that affect ATP binding impair the induction of cell proliferation. We also show that increased expression levels of KSR1 decrease the responsiveness to the KRASG12C inhibitor sotorasib in human cancer cell lines, thus suggesting that increased levels of expression of KSR may make tumour cells less dependent on KRAS oncogenic signalling.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipWe thank M. San Roman and R. Villar for technical assistance. This work was supported by grants from the European Research Council (ERC-AG/695566, THERACAN), the Spanish Ministry of Science, Innovation and Universities (RTI2018-094664-B-I00 and RTC2017-6576-1), the Autonomous Community of Madrid (B2017/BMD-3884 iLUNG-CM), the CRIS Cancer Foundation and the Asociacion Espanola contra el Cancer (AECC) (GC166173694BARB). MB is a recipient of an Endowed Chair from the AXA Research Fund. GP has been supported by a fellowship from the Programa de Atraccion de Talento of the Autonomous Community of Madrid. SGA is a recipient of a postdoctoral fellowship from the AECC. OB is a recipient of a fellowship from the Formacion de Personal Investigador (FPI) program of the Spanish Ministry of Science, Innovation and Universities.es_ES
dc.identifier.citationMol Oncol . 2022 Mar 21.es_ES
dc.identifier.doi10.1002/1878-0261.13213es_ES
dc.identifier.e-issn1878-0261es_ES
dc.identifier.journalMolecular oncologyes_ES
dc.identifier.pubmedID35313064es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/14701
dc.language.isoenges_ES
dc.publisherWileyes_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/RTI2018-094664-B-I00es_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/RTC2017-6576-1es_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ES/B2017/BMD-3884 iLUNG-CMes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/695566/EUes_ES
dc.relation.publisherversionhttps://doi.org/10.1002/1878-0261.13213es_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Oncología Experimentales_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectATP bindinges_ES
dc.subjectKRAS(G12C)es_ES
dc.subjectMAPK pathwayes_ES
dc.subjectRAS-independent proliferationes_ES
dc.subjectresistancees_ES
dc.subjectsotorasibes_ES
dc.titleKSR induces RAS-independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors.es_ES
dc.typejournal articlees_ES
dc.type.hasVersionVoRes_ES
dspace.entity.typePublication
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relation.isAuthorOfPublication3064b65c-f19a-4726-a7c1-a4d1664329be
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relation.isAuthorOfPublication.latestForDiscoveryaff72b01-c3b6-455f-b4d5-abd12819cadb
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