Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR

Anirudh Prahallad, Chong Sun, Sidong Huang, Federica Di Nicolantonio, Ramon Salazar, Davide Zecchin, Roderick L. Beijersbergen, Alberto Bardelli, René Bernards

Research output: Contribution to journalArticle

1057 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)100-104
Number of pages5
JournalNature
Volume483
Issue number7387
DOIs
Publication statusPublished - Mar 1 2012

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Epidermal Growth Factor Receptor
Colonic Neoplasms
Melanoma
Pharmaceutical Preparations
Oncogene Proteins
Therapeutic Uses
RNA Interference
Colon
Phosphotransferases
Therapeutics
PLX4032
Antibodies
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., ... Bernards, R. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature, 483(7387), 100-104. https://doi.org/10.1038/nature10868

Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. / Prahallad, Anirudh; Sun, Chong; Huang, Sidong; Di Nicolantonio, Federica; Salazar, Ramon; Zecchin, Davide; Beijersbergen, Roderick L.; Bardelli, Alberto; Bernards, René.

In: Nature, Vol. 483, No. 7387, 01.03.2012, p. 100-104.

Research output: Contribution to journalArticle

Prahallad, A, Sun, C, Huang, S, Di Nicolantonio, F, Salazar, R, Zecchin, D, Beijersbergen, RL, Bardelli, A & Bernards, R 2012, 'Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR', Nature, vol. 483, no. 7387, pp. 100-104. https://doi.org/10.1038/nature10868
Prahallad, Anirudh ; Sun, Chong ; Huang, Sidong ; Di Nicolantonio, Federica ; Salazar, Ramon ; Zecchin, Davide ; Beijersbergen, Roderick L. ; Bardelli, Alberto ; Bernards, René. / Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. In: Nature. 2012 ; Vol. 483, No. 7387. pp. 100-104.
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