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 | Silva Almeida Ribeiro, MF | |
dc.contributor.author | 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 | 2024-07-17T13:49:43Z | |
dc.date.available | 2020-12-07 | |
dc.date.available | 2024-07-17T13:49:43Z | |
dc.date.issued | 2020-12-11 | |
dc.identifier.citation | Knebel, F.H.; Barber, L.J.; Newey, A.; Kleftogiannis, D.; Woolston, A.; Griffiths, B.; Fenwick, K.; Bettoni, F.; Ribeiro, M.F.S.A.; da Fonseca, L.; et al. Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy. Cancers 2020, 12, 3736. https://doi.org/10.3390/cancers12123736 | en_US |
dc.identifier.other | ARTN 3736 | |
dc.identifier.other | ARTN 3736 | |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/98193 | |
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. | en_US |
dc.publisher | MDPI | en_US |
dc.relation.ispartof | CANCERS | |
dc.rights | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). | |
dc.subject | colorectal cancer | en_US |
dc.subject | ctDNA-Sequencing | en_US |
dc.subject | ctDNA-ddPCR | en_US |
dc.subject | acquired resistance | en_US |
dc.subject | genetic resistance-gap | en_US |
dc.subject | EGFR-antibodies | en_US |
dc.title | Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy | en_US |
dc.type | Article | en_US |
dc.rights.holder | © 2020 by the authors. Licensee MDPI, Basel, Switzerland. | |
dc.identifier.doi | 10.3390/cancers12123736 | |
pubs.author-url | https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000601704600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=612ae0d773dcbdba3046f6df545e9f6a | en_US |
pubs.issue | 12 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 12 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |
qmul.funder | Deciphering and predicting the evolution of cancer cell populations::European Research Council | en_US |
rioxxterms.funder.project | b215eee3-195d-4c4f-a85d-169a4331c138 | en_US |