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Cancer Research 67, 2643, March 15, 2007. doi: 10.1158/0008-5472.CAN-06-4158
© 2007 American Association for Cancer Research
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Molecular Biology, Pathobiology, and Genetics

Oncogenic Activation of the RAS/RAF Signaling Pathway Impairs the Response of Metastatic Colorectal Cancers to Anti–Epidermal Growth Factor Receptor Antibody Therapies

Silvia Benvenuti1, Andrea Sartore-Bianchi2, Federica Di Nicolantonio1, Carlo Zanon1, Mauro Moroni2, Silvio Veronese2, Salvatore Siena2 and Alberto Bardelli1,3

1 Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy; 2 The Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda; and 3 FIRC Institute of Molecular Oncology, Milan, Italy

Requests for reprints: Alberto Bardelli, Laboratory of Molecular Genetics Institute for Cancer Research and Treatment, University of Torino Medical School, Strada Provinciale 142, Km 3.95, Candiolo (Torino) 10060, Italy. Phone: 0039-011-99333601; E-mail: a.bardelli{at}unito.it or Salvatore Siena, Divisione Oncologia Medica Falck, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore, 320162 Milan, Italy. E-mail: salvatore.siena{at}ospedaleniguarda.it.

Monoclonal antibodies (mAbs) against the extracellular domain of the epidermal growth factor receptor (EGFR) have been introduced for the treatment of metastatic colorectal cancer (mCRC). We have reported recently that increased copy number of the EGFR can predict response to anti-EGFR mAbs and that patients might be selected for treatment based on EGFR copy number. Here, we show that mutations activating the RAS/RAF signaling pathway are also predictive and prognostic indicators in mCRC patients, being inversely correlated with response to anti-EGFR mAbs. In cellular models of CRCs, activation of the RAS signaling pathway by introduction of an activated K-RAS allele (Gly12Val) impairs the therapeutic effect of anti-EGFR mAbs. In cancer cells carrying constitutively active RAS, the pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) signaling cascade improves anti-EGFR treatment based on mAbs. These results have implications for the identification of patients who are likely to respond to anti-EGFR treatment. They also provide the rationale for combination therapies, targeted simultaneously to the EGFR and RAS/RAF/MAPK signaling pathways in CRC patients. [Cancer Res 2007;67(6):2643–8]




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