dc.contributor.author | Georgiou, A | |
dc.contributor.author | Stewart, A | |
dc.contributor.author | Cunningham, D | |
dc.contributor.author | Banerji, U | |
dc.contributor.author | Whittaker, SR | |
dc.date.accessioned | 2020-03-24T12:47:06Z | |
dc.date.issued | 2020-06-01 | |
dc.identifier.citation | Molecular cancer research : MCR, 2020, 18 (6), pp. 835 - 846 | |
dc.identifier.issn | 1541-7786 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3552 | |
dc.identifier.eissn | 1557-3125 | |
dc.identifier.doi | 10.1158/1541-7786.mcr-19-1201 | |
dc.description.abstract | Through the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in NRAS/KRAS/BRAFV600 -wild-type colorectal cancer cells. Reduced NF1 expression permitted sustained signaling through the MAPK pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition leads to synergistic antiproliferative activity. Human KRAS/NRAS/BRAFV600 -wild-type colorectal cancer cell lines with NF1 mutations displayed reduced NF1 mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in PTEN were associated with resistance to dual EGFR/MEK inhibition but cotreatment with a PI3K inhibitor further suppressed proliferation. Loss of NF1 may be a useful biomarker to identify patients that are less likely to benefit from single-agent anti-EGFR therapy in colorectal cancer and may direct potential combination strategies. IMPLICATIONS: This study suggests that further clinical validation of NF1 status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with KRAS/NRAS/BRAFV600 -wild-type tumors is warranted. | |
dc.format | Print-Electronic | |
dc.format.extent | 835 - 846 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.title | Inactivation of NF1 Promotes Resistance to EGFR Inhibition in KRAS/NRAS/BRAFV600 -Wild-Type Colorectal Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-02-20 | |
rioxxterms.versionofrecord | 10.1158/1541-7786.mcr-19-1201 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2020-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Molecular cancer research : MCR | |
pubs.issue | 6 | |
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/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 18 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
dc.contributor.icrauthor | Banerji, Udai | |