Publication Date:
2012-01-28
Description:
Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, we find that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10% of all colon cancers), for which there are currently no targeted treatment options available, might benefit from combination therapy consisting of BRAF and EGFR inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Prahallad, Anirudh -- Sun, Chong -- Huang, Sidong -- Di Nicolantonio, Federica -- Salazar, Ramon -- Zecchin, Davide -- Beijersbergen, Roderick L -- Bardelli, Alberto -- Bernards, Rene -- England -- Nature. 2012 Jan 26;483(7387):100-3. doi: 10.1038/nature10868.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Carcinogenesis, Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22281684" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antibodies, Monoclonal/pharmacology
;
Antibodies, Monoclonal, Humanized
;
Antineoplastic Agents/pharmacology/therapeutic use
;
Apoptosis/drug effects
;
Cell Line, Tumor
;
Cell Proliferation/drug effects
;
Cetuximab
;
Colorectal Neoplasms/*drug therapy/*enzymology/genetics/pathology
;
Drug Resistance, Neoplasm/*drug effects
;
Drug Synergism
;
Enzyme Activation/drug effects
;
Erlotinib Hydrochloride
;
Feedback, Physiological/*drug effects
;
Female
;
HEK293 Cells
;
Humans
;
Indoles/pharmacology/therapeutic use
;
Melanoma/drug therapy/metabolism
;
Mice
;
Protein Kinase Inhibitors/pharmacology/therapeutic use
;
Proto-Oncogene Proteins B-raf/*antagonists &
;
inhibitors/chemistry/*genetics/metabolism
;
Quinazolines/pharmacology/therapeutic use
;
RNA Interference
;
Receptor, Epidermal Growth Factor/*agonists/antagonists & inhibitors/metabolism
;
Sulfonamides/pharmacology/therapeutic use
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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