title: The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies.
abstract: The activity of the epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab in metastatic colorectal carcinoma (mCRC) is significantly limited by molecular mechanisms leading to intrinsic or acquired resistance. The S492R mutation of the EGFR, which is caused by either the 1476C>A or the 1474A>C substitution, interferes with binding to cetuximab but not to panitumumab, and has been detected in mCRC with acquired resistance to cetuximab. Since mechanisms of acquired and intrinsic resistance to EGFR monoclonal antibodies in CRC significantly overlap, we evaluated the frequency of the S492R mutation in a series of KRAS-exon 2 wild-type CRC patients. Genomic DNA was extracted from formalin fixed paraffin embedded (FFPE) tissues that were obtained from 505 systemic therapy-naïve CRC patients. A PCR/sequencing method for the detection of the S492R mutation was developed, by using as positive control a plasmid in which the 1474A>C mutation was generated by site directed mutagenesis. The lowest level of detection of this assay was approximately 10% mutant DNA in a background of wild-type DNA. PCR sequencing analysis revealed no S492R mutations in any of the analyzed 505 CRC specimens. Our findings suggest that the S492R mutation is not involved in primary resistance to cetuximab in CRC. Therefore, patients with mCRC should not be routinely screened for this mutation prior therapy with cetuximab.
authors.affiliation: Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM); Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Mercogliano (AV), Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Esposito
authors.affiliation: Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM); Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Mercogliano (AV), Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Rachiglio
authors.affiliation: Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM); Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Mercogliano (AV), Italy.
authors.forename: Maria Libera
authors.initials: ML
authors.lastname: La Porta
authors.affiliation: Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM); Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Mercogliano (AV), Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sacco
authors.affiliation: Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM); Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Mercogliano (AV), Italy.
authors.forename: Cristin
authors.initials: C
authors.lastname: Roma
authors.affiliation: Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM); Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Mercogliano (AV), Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Iannaccone
authors.affiliation: Surgical Pathology Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Naples, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Tatangelo
authors.affiliation: Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM); Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Mercogliano (AV), Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Forgione
authors.affiliation: Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM); Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Mercogliano (AV), Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Pasquale
authors.affiliation: Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM); Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Mercogliano (AV), Italy.
authors.forename: Americo
authors.initials: A
authors.lastname: Barbaro
authors.affiliation: Surgical Pathology Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Naples, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.affiliation: Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara"; Seconda Università degli Studi di Napoli; Napoli, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS; Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077544:Panitumumab; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab
keywords: EGFR; cetuximab; colon carcinoma; monoclonal antibodies; panitumumab; resistance
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