dc.contributor.author | Knebel, FH | |
dc.contributor.author | Barber, LJ | |
dc.contributor.author | Newey, A | |
dc.contributor.author | Kleftogiannis, D | |
dc.contributor.author | Woolston, A | |
dc.contributor.author | Griffiths, B | |
dc.contributor.author | Fenwick, K | |
dc.contributor.author | Bettoni, F | |
dc.contributor.author | Ribeiro, MFSA | |
dc.contributor.author | da Fonseca, L | |
dc.contributor.author | Costa, F | |
dc.contributor.author | Capareli, FC | |
dc.contributor.author | Hoff, PM | |
dc.contributor.author | Sabbaga, J | |
dc.contributor.author | Camargo, AA | |
dc.contributor.author | Gerlinger, M | |
dc.date.accessioned | 2021-01-08T15:31:50Z | |
dc.date.issued | 2020-12-11 | |
dc.identifier.citation | Cancers, 2020, 12 (12) | |
dc.identifier.issn | 2072-6694 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4269 | |
dc.identifier.eissn | 2072-6694 | |
dc.identifier.doi | 10.3390/cancers12123736 | |
dc.description.abstract | Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with RAS wild-type metastatic colorectal cancer (mCRC), but resistance invariably occurs. Previous data showed that only a minority of cancer cells harboured known genetic resistance drivers when clinical resistance to single-agent EGFR-Abs had evolved, supporting the activity of non-genetic resistance mechanisms. Here, we used error-corrected ctDNA-sequencing (ctDNA-Seq) of 40 cancer genes to identify drivers of resistance and whether a genetic resistance-gap (a lack of detectable genetic resistance mechanisms in a large fraction of the cancer cell population) also occurs in RAS wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one MAP2K1/MEK1 mutation and one ERBB2 amplification in 2/3 patients with primary resistance and KRAS, NRAS, MAP2K1/MEK1 mutations and ERBB2 aberrations in 6/7 patients with acquired resistance. In vitro testing identified MAP2K1/MEK1 P124S as a novel driver of EGFR-Ab resistance. Mutation subclonality analyses confirmed a genetic resistance-gap in mCRCs treated with EGFR-Abs and chemotherapy, with only 13.42% of cancer cells harboring identifiable resistance drivers. Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours. | |
dc.format | Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | MDPI | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-12-07 | |
rioxxterms.versionofrecord | 10.3390/cancers12123736 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-12-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancers | |
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/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics | |
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/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics | |
pubs.publication-status | Published | |
pubs.volume | 12 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Translational Oncogenomics | |
dc.contributor.icrauthor | Woolston, Andrew | |
dc.contributor.icrauthor | Gerlinger, Marco | |