dc.contributor.author | Georgiou, A | |
dc.contributor.author | Stewart, A | |
dc.contributor.author | Vlachogiannis, G | |
dc.contributor.author | Pickard, L | |
dc.contributor.author | Valeri, N | |
dc.contributor.author | Cunningham, D | |
dc.contributor.author | Whittaker, SR | |
dc.contributor.author | Banerji, U | |
dc.date.accessioned | 2021-09-07T08:28:37Z | |
dc.date.available | 2021-09-07T08:28:37Z | |
dc.date.issued | 2021-08-30 | |
dc.identifier | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000691219400002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=d4b848928d1c3e5c86d298abb68475f9 | |
dc.identifier.citation | CELLULAR ONCOLOGY, 2021, pp. ? - ? (10) | |
dc.identifier.issn | 2211-3428 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4793 | |
dc.identifier.eissn | 2211-3436 | |
dc.identifier.doi | 10.1007/s13402-021-00628-7 | |
dc.description.abstract | PURPOSE: We hypothesised that plasticity in signal transduction may be a mechanism of drug resistance and tested this hypothesis in the setting of cetuximab resistance in patients with KRAS/NRAS/BRAFV600 wild-type colorectal cancer (CRC). METHODS: A multiplex antibody-based platform was used to study simultaneous changes in signal transduction of 55 phospho-proteins in 12 KRAS/NRAS/BRAFV600 wild-type CRC cell lines (6 cetuximab sensitive versus 6 cetuximab resistant) following 1 and 4 h in vitro cetuximab exposure. We validated our results in CRC patient samples (n = 4) using ex vivo exposure to cetuximab in KRAS/NRAS/BRAFV600 cells that were immunomagnetically separated from the serous effusions of patients with known cetuximab resistance. RESULTS: Differences in levels of phospho-proteins in cetuximab sensitive and resistant cell lines included reductions in phospho-RPS6 and phospho-PRAS40 in cetuximab sensitive, but not cetuximab resistant cell lines at 1 and 4 h, respectively. In addition, phospho-AKT levels were found to be elevated in 3/4 patient samples following ex vivo incubation with cetuximab for 1 h. We further explored these findings by studying the effects of combinations of cetuximab and two PI3K pathway inhibitors in 3 cetuximab resistant cell lines. The addition of PI3K pathway inhibitors to cetuximab led to a significantly higher reduction in colony formation capacity compared to cetuximab alone. CONCLUSION: Our findings suggest activation of the PI3K pathway as a mechanism of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type CRC. | |
dc.format.extent | ? - ? (10) | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | SPRINGER | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Science & Technology | |
dc.subject | Life Sciences & Biomedicine | |
dc.subject | Oncology | |
dc.subject | Cell Biology | |
dc.subject | Pathology | |
dc.subject | Colorectal cancer | |
dc.subject | Cetuximab | |
dc.subject | Proteomics | |
dc.subject | Phospho-proteomics | |
dc.subject | Signalling adaptations | |
dc.subject | Resistance mechanisms | |
dc.subject | 1ST-LINE TREATMENT | |
dc.subject | IRINOTECAN | |
dc.subject | KRAS | |
dc.subject | INHIBITOR | |
dc.subject | RAS | |
dc.subject | FLUOROURACIL | |
dc.subject | CHEMOTHERAPY | |
dc.subject | LEUCOVORIN | |
dc.subject | IMPACT | |
dc.title | A phospho-proteomic study of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type colorectal cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-07-27 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1007/s13402-021-00628-7 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2021-08-30 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | CELLULAR ONCOLOGY | |
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/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
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/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
icr.researchteam | Gastrointestinal Cancer Biology and Genomics | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
icr.researchteam | Gastrointestinal Cancer Biology and Genomics | |
dc.contributor.icrauthor | Valeri, Nicola | |
dc.contributor.icrauthor | Banerji, Udai | |