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Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy.

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Publication Date
2020-12-11
ICR Author
Barber, Louise
Gerlinger, Marco
Author
Knebel, FH
Barber, LJ
Newey, A
Kleftogiannis, D
Woolston, A
Griffiths, B
Fenwick, K
Bettoni, F
Ribeiro, MFSA
da Fonseca, L
Costa, F
Capareli, FC
Hoff, PM
Sabbaga, J
Camargo, AA
Gerlinger, M
Type
Journal Article
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Abstract
Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with <i>RAS</i> 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 <i>RAS</i> wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one <i>MAP2K1/MEK1</i> mutation and one <i>ERBB2</i> amplification in 2/3 patients with primary resistance and <i>KRAS, NRAS, MAP2K1/MEK1</i> mutations and <i>ERBB2</i> 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 <i>MAP2K1</i> mutations could inform trials of MEK-inhibitors in these tumours.
URL
https://repository.icr.ac.uk/handle/internal/4269
Collections
  • Molecular Pathology
Licenseref URL
https://creativecommons.org/licenses/by/4.0
Version of record
10.3390/cancers12123736
Research team
Translational Oncogenomics
Language
eng
Date accepted
2020-12-07
License start date
2020-12-11
Citation
Cancers, 2020, 12 (12)

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