Reference Detail


Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at :

Ref Type Journal Article
PMID (33322618)
Authors 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
Title Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy.
Abstract Text 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.


  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")


  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
MAP2K1 P124S missense unknown MAP2K1 P124S lies within the protein kinase domain of the Map2k1 protein ( P124S results in increased Erk1/2 phosphorylation and confers resistance to Mek and Braf inhibitors (PMID: 19915144, PMID: 22197931) and an Egfr antibody (PMID: 33322618) in culture, but has similar induction of cell proliferation and viability levels to wild-type Map2k1 in culture (PMID: 29533785), and therefore, its effect on Map2k1 protein function is unknown. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 P124S colorectal cancer predicted - resistant Cetuximab + Irinotecan Case Reports/Case Series Actionable In a clinical case study, a patient with KRAS/NRAS-wild-type colorectal cancer who progressed on treatment with Erbitux (cetuximab) and Camptosar (irinotecan) was found through ctDNA testing to have acquired MAP2K1 P124S, and preclinical analysis of colorectal cancer cells expressing MAP2K1 P124S demonstrated increased Erk phosphorylation upon treatment with Erbitux (cetuximab) in culture (PMID: 33322618). 33322618