Oncotarget

Research Papers:

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

Anna-Lena Geißler, Miriam Geißler, Daniel Kottmann, Lisa Lutz, Christiane D. Fichter, Ralph Fritsch, Britta Weddeling, Frank Makowiec, Martin Werner and Silke Lassmann _

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Oncotarget. 2017; 8:17164-17190. https://doi.org/10.18632/oncotarget.15211

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Abstract

Anna-Lena Geißler1,2,3,4, Miriam Geißler1,2,3, Daniel Kottmann1,2,3, Lisa Lutz1,2, Christiane D. Fichter1,2,3, Ralph Fritsch2,5,7, Britta Weddeling1,7, Frank Makowiec2,6,7, Martin Werner1,2,4,7, Silke Lassmann1,2,4,7,8

1Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany

2Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany

3Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany

4German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

5Department of Internal Medicine, University of Freiburg, Freiburg im Breisgau, Germany

6Department of Surgery, University of Freiburg, Freiburg im Breisgau, Germany

7Comprehensive Cancer Center Freiburg, All Medical Center – University of Freiburg, Freiburg im Breisgau, Germany

8BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg im Breisgau, Germany

Correspondence to:

Silke Lassmann, email: silke.lassmann@uniklinik-freiburg.de

Keywords: anti-EGFR therapy, next generation sequencing, predictive markers, colorectal cancer (CRC), E-cadherin

Received: July 11, 2016     Accepted: January 16, 2017     Published: February 09, 2017

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.


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