title: Circulating pEGFR is a candidate response biomarker of cetuximab therapy in colorectal cancer.
abstract: OBJECTIVE
  The lack of secreted biomarkers measurable by noninvasive tests hampers the development of effective targeted therapies against cancer. Our hypothesis is that cetuximab (an anti-EGFR mAb) induces a specific secretome in colorectal cancer cells that could be exploited for biomarker discovery.
  
  
  METHODS
  Considering the strong correlation between mutated KRAS and a lack of response to cetuximab therapy, we addressed whether performing secretome-based proteomics on isogenic colorectal cancer cells sharing the KRAS mutations found on patients would yield candidate-secreted biomarkers useful in the clinical setting. Because 2D culture did not optimally model the sensitivity/resistance to cetuximab observed in colorectal cancer patients, we moved to 3D spheroids, developing a methodology for both cell-based assays and quantitative proteomics.
  
  
  RESULTS
  A large comparative quantitative proteomic analysis of the 3D secretomes of colorectal cancer isogenic cells treated with cetuximab uncovered an EGFR pathway-centric secretome found only when cells grow in 3D. The validation of the secretome findings in plasma of colorectal cancer patients, suggests that phosphorylated-EGFR (pEGFR) is a candidate-secreted biomarker of response to cetuximab.
  
  
  CONCLUSIONS
  We have proved that 3D spheroids from colorectal cancer cells generate secretomes with a drug-sensitivity profile that correlates well with patients with colorectal cancer, illustrating molecular connections between intracellular and extracellular signaling. Furthermore, we show how the secretion of pEGFR is associated with the sensitivity of colorectal cancer cells to cetuximab and the response of patients with colorectal cancer to the drug. Our work could allow the noninvasive monitoring of anti-EGFR treatment in patients with colorectal cancer.
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Theodora
authors.initials: T
authors.lastname: Katsila
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Juliachs
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. Statistics Department. University of Barcelona (UB), Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Gregori
authors.affiliation: Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Villarreal
authors.affiliation: IRCC, Institute for Cancer Research and Treatment at Candiolo, University of Torino, Candiolo, Italy. FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Horizon Discovery Ltd., Cambridge Research Park, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Torrance
authors.affiliation: Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Elez
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. jvillanueva@vhio.net.
authors.forename: Josep
authors.initials: J
authors.lastname: Villanueva
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000068818:Cetuximab; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000097:blood* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D020543:Proteome; D040901:Proteomics; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D020543:Proteome; D066246:ErbB Receptors; D018631:ras Proteins; D000068818:Cetuximab