Document Detail


KRAS p.G13D mutations are associated with sensitivity to anti-EGFR antibody treatment in colorectal cancer cell lines.
MedLine Citation:
PMID:  23015072     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Isabelle Messner; Giuseppe Cadeddu; Wolfgang Huckenbeck; Helen J Knowles; Helmut E Gabbert; Stephan E Baldus; Karl-Ludwig Schaefer
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-27
Journal Detail:
Title:  Journal of cancer research and clinical oncology     Volume:  139     ISSN:  1432-1335     ISO Abbreviation:  J. Cancer Res. Clin. Oncol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-21     Completed Date:  2013-03-14     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  7902060     Medline TA:  J Cancer Res Clin Oncol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  201-9     Citation Subset:  IM    
Affiliation:
Medical Faculty, Institute of Pathology, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal / pharmacology*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Colorectal Neoplasms / genetics*,  metabolism
Drug Resistance, Neoplasm / genetics*
Gene Expression Regulation, Neoplastic
Humans
Mutation*
Phosphatidylinositol 3-Kinases / genetics,  metabolism
Proto-Oncogene Proteins / genetics*,  metabolism
Proto-Oncogene Proteins B-raf / genetics,  metabolism
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  genetics,  metabolism
ras Proteins / genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
MP/19200//Arthritis Research UK
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antineoplastic Agents; 0/KRAS protein, human; 0/Proto-Oncogene Proteins; 0/panitumumab; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.137/PIK3CA protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.1/BRAF protein, human; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 3.6.5.2/ras Proteins; PQX0D8J21J/cetuximab

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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