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KRAS p.G13D mutations are associated with sensitivity to anti-EGFR antibody treatment in colorectal cancer cell lines

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Abstract

Purpose

Targeted therapies using the anti-EGFR antibodies panitumumab (Pmab) or cetuximab (Cmab) are currently restricted to patients with metastatic colorectal adenocarcinoma whose tumours do not show a mutation in KRAS. However, recent retrospective studies indicated that patients with tumours mutated in codon 13 of KRAS may benefit from treatment with Cmab in contrast to patients with tumours mutated in KRAS codon 12.

Methods

To study the functional impact of the subtype of KRAS mutations on the efficiency of EGFR-targeted therapies, we correlated the KRAS mutation status of 15 colorectal carcinoma cell lines with the in vitro sensitivity of these cells to Cmab/Pmab. Mutations in the potential predictive biomarkers BRAF and PIK3CA as well as protein expression of EGFR and PTEN were also determined.

Results

Four out of seven KRAS-mutated cell lines were characterised by the p.G13D mutation. Treatment of these cells using Cmab/Pmab induced a significant growth inhibition in contrast to cell lines showing a KRAS mutation at codon 12 or 61. Out of the eight KRAS wild-type cell lines, five were insensitive to Cmab/Pmab. These cell lines were characterised either by BRAF mutation or by absence of EGFR or PTEN protein expression.

Conclusions

Since KRAS p.G13D-mutated tumour cells may respond to EGFR-targeted therapy, we suggest including subtype analysis of KRAS mutations in prospective clinical trials. In KRAS wild-type tumour cells, BRAF mutations and loss of EGFR or PTEN expression may lead to resistance to EGFR-targeted therapy and should be considered as additional negative predictive biomarkers.

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Acknowledgments

The study was supported by the “Forschungskommission” of the Medical Faculty of the University of Duesseldorf (KLS, SEB, project 9772442). HJK is supported by Arthritis Research UK (MP/19200).

Conflict of interest

None declared.

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Authors and Affiliations

  1. Medical Faculty, Institute of Pathology, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany

    Isabelle Messner, Giuseppe Cadeddu, Helmut E. Gabbert, Stephan E. Baldus & Karl-Ludwig Schaefer

  2. Medical Faculty, Institute of Forensic Medicine, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany

    Wolfgang Huckenbeck

  3. Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Oxford, OX3 7LD, UK

    Helen J. Knowles

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  1. Isabelle Messner
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  2. Giuseppe Cadeddu
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  3. Wolfgang Huckenbeck
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  4. Helen J. Knowles
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  5. Helmut E. Gabbert
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  6. Stephan E. Baldus
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  7. Karl-Ludwig Schaefer
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Correspondence to Karl-Ludwig Schaefer.

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Messner, I., Cadeddu, G., Huckenbeck, W. et al. KRAS p.G13D mutations are associated with sensitivity to anti-EGFR antibody treatment in colorectal cancer cell lines. J Cancer Res Clin Oncol 139, 201–209 (2013). https://doi.org/10.1007/s00432-012-1319-7

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  • DOI: https://doi.org/10.1007/s00432-012-1319-7

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