dc.contributor.author | Whittaker, SR | |
dc.contributor.author | Cowley, GS | |
dc.contributor.author | Wagner, S | |
dc.contributor.author | Luo, F | |
dc.contributor.author | Root, DE | |
dc.contributor.author | Garraway, LA | |
dc.date.accessioned | 2020-07-23T15:01:30Z | |
dc.date.issued | 2015-12-01 | |
dc.identifier.citation | Molecular cancer therapeutics, 2015, 14 (12), pp. 2700 - 2711 | |
dc.identifier.issn | 1535-7163 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3853 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.doi | 10.1158/1535-7163.mct-15-0136-t | |
dc.description.abstract | RAF and MEK inhibitors are effective in BRAF-mutant melanoma but not in BRAF-mutant colorectal cancer. To gain additional insights into this difference, we performed a genome-scale pooled shRNA enhancer screen in a BRAF-mutant, RAF inhibitor-resistant colorectal cancer cell line exposed to the selective RAF inhibitor PLX4720. We identified multiple genes along the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) signaling axis that, when suppressed, either genetically or pharmacologically, sensitized cells to the selective RAF inhibitor through sustained inhibition of MAPK signaling. Strikingly, CRAF was a key mediator of resistance that could be overcome by the use of pan-RAF inhibitors in combination with a MEK inhibitor. Furthermore, the combination of pan-RAF and MEK inhibitors displayed strong synergy in melanoma and colorectal cancer cell lines with RAS-activating events such as RTK activation, KRAS mutation, or NF1 loss-of-function mutations. Combinations of selective RAF inhibitors, such as PLX4720 or dabrafenib, with MEK inhibitors did not incur such profound synergy, suggesting that inhibition of CRAF by pan-RAF inhibitors plays a key role in determining cellular response. Importantly, in contrast to the modest activity seen with single-agent treatment, dual pan-RAF and MEK inhibition results in the induction of apoptosis, greatly enhancing efficacy. Notably, combined pan-RAF and MEK inhibition can overcome intrinsic and acquired resistance to single-agent RAF/MEK inhibition, supporting dual pan-RAF and MEK inhibition as a novel therapeutic strategy for BRAF- and KRAS-mutant cancers. | |
dc.format | Print-Electronic | |
dc.format.extent | 2700 - 2711 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Sulfonamides | |
dc.subject | Indoles | |
dc.subject | MAP Kinase Kinase Kinases | |
dc.subject | raf Kinases | |
dc.subject | Proto-Oncogene Proteins B-raf | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Apoptosis | |
dc.subject | MAP Kinase Signaling System | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Mutation | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.title | Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2015-08-30 | |
rioxxterms.versionofrecord | 10.1158/1535-7163.mct-15-0136-t | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2015-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Molecular cancer therapeutics | |
pubs.issue | 12 | |
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 Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Drug Resistance | |
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 Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Drug Resistance | |
pubs.publication-status | Published | |
pubs.volume | 14 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Molecular Drug Resistance | |
dc.contributor.icrauthor | Whittaker, Steven | |
dc.contributor.icrauthor | Wagner, Steve | |