ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer.

Autor:	Geißler AL; 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., Geißler M; 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., Kottmann D; 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., Lutz L; Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.; Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Fichter CD; 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., Fritsch R; 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., Weddeling B; 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., Makowiec F; 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., Werner M; 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., Lassmann S; 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.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2017 Mar 07; Vol. 8 (10), pp. 17164-17190.
DOI:	10.18632/oncotarget.15211
Abstrakt:	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.
Databáze:	MEDLINE
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