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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.
Journal Cancers
Vol 12
Issue 12
Date 2020 Dec 11
URL
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.

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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 (UniProt.org). The functional effect of P124S is conflicting, as it has been reported to confer a gain of function on the Map2k1 protein as demonstrated by increased Erk1/2 phosphorylation, but has similar induction of cell proliferation and viability levels as wild-type Map2k1 (PMID: 29533785), and confers resistance to Mek and Braf inhibitors in melanoma cells (PMID: 19915144, PMID: 22197931), and an Egfr antibody in colorectal cancer cells (PMID: 33322618). 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