title: ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer.
abstract: EGFR-targeted therapy is a key treatment approach in patients with RAS wildtype metastatic colorectal cancers (CRC). Still, also RAS wildtype CRC may be resistant to EGFR-targeted therapy, with few predictive markers available for improved stratification of patients. Here, we investigated response of 7 CRC cell lines (Caco-2, DLD1, HCT116, HT29, LS174T, RKO, SW480) to Cetuximab and correlated this to NGS-based mutation profiles, EGFR promoter methylation and EGFR expression status as well as to E-cadherin expression. Moreover, tissue specimens of primary and/or recurrent tumors as well as liver and/or lung metastases of 25 CRC patients having received Cetuximab and/or Panitumumab were examined for the same molecular markers. In vitro and in situ analyses showed that EGFR promoter methylation and EGFR expression as well as the MSI and or CIMP-type status did not guide treatment responses. In fact, EGFR-targeted treatment responses were also observed in RAS exon 2 p.G13 mutated CRC cell lines or CRC cases and were further linked to PIK3CA exon 9 mutations. In contrast, non-response to EGFR-targeted treatment was associated with ATM mutations and low E-cadherin expression. Moreover, down-regulation of E-cadherin by siRNA in otherwise Cetuximab responding E-cadherin positive cells abrogated their response. Hence, we here identify ATM and E-cadherin expression as potential novel supportive predictive markers for EGFR-targeted therapy.
authors.affiliation: Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Geißler
authors.affiliation: Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Geißler
authors.affiliation: Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kottmann
authors.affiliation: Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lutz
authors.affiliation: Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Christiane D
authors.initials: CD
authors.lastname: Fichter
authors.affiliation: Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|Department of Internal Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Fritsch
authors.affiliation: Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.|Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Weddeling
authors.affiliation: Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|Department of Surgery, University of Freiburg, Freiburg im Breisgau, Germany.|Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Makowiec
authors.affiliation: Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.affiliation: Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.|Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.|BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Lassmann
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D018938:Caco-2 Cells; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000068818:Cetuximab / Q000494:pharmacology / Q000627:therapeutic use; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; D015820:Cadherins; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000068818:Cetuximab
keywords: E-cadherin; anti-EGFR therapy; colorectal cancer (CRC); next generation sequencing; predictive markers