dc.contributor.author | Jones, GG | |
dc.contributor.author | Del Río, IB | |
dc.contributor.author | Sari, S | |
dc.contributor.author | Sekerim, A | |
dc.contributor.author | Young, LC | |
dc.contributor.author | Hartig, N | |
dc.contributor.author | Areso Zubiaur, I | |
dc.contributor.author | El-Bahrawy, MA | |
dc.contributor.author | Hynds, RE | |
dc.contributor.author | Lei, W | |
dc.contributor.author | Molina-Arcas, M | |
dc.contributor.author | Downward, J | |
dc.contributor.author | Rodriguez-Viciana, P | |
dc.date.accessioned | 2020-06-03T14:17:00Z | |
dc.date.issued | 2019-06-10 | |
dc.identifier.citation | Nature communications, 2019, 10 (1), pp. 2532 - ? | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3693 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-019-10367-x | |
dc.description.abstract | Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by dephosphorylating a critical inhibitory site on RAF kinases. Here we show that genetic inhibition of SHOC2 suppresses tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines and prominently inhibits tumour development in autochthonous murine KRAS-driven lung cancer models. On the other hand, systemic SHOC2 ablation in adult mice is relatively well tolerated. Furthermore, we show that SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Mechanistically, SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression that promotes BIM-dependent apoptosis. These results present a rationale for the generation of SHOC2 phosphatase targeted therapies, both as a monotherapy and to widen the therapeutic index of MEK inhibitors. | |
dc.format | Electronic | |
dc.format.extent | 2532 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Mice, Knockout | |
dc.subject | Humans | |
dc.subject | Mice, Nude | |
dc.subject | Carcinoma, Non-Small-Cell Lung | |
dc.subject | Lung Neoplasms | |
dc.subject | ras Proteins | |
dc.subject | raf Kinases | |
dc.subject | Intracellular Signaling Peptides and Proteins | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Neoplasm Transplantation | |
dc.subject | Apoptosis | |
dc.subject | MAP Kinase Signaling System | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Mutation | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Protein Multimerization | |
dc.subject | HEK293 Cells | |
dc.title | SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-05-08 | |
rioxxterms.versionofrecord | 10.1038/s41467-019-10367-x | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-06-10 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature communications | |
pubs.issue | 1 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group | |
pubs.publication-status | Published | |
pubs.volume | 10 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Lung Cancer Group | en_US |
dc.contributor.icrauthor | Downward, Julian David Harry | |