Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti–epidermal growth factor receptor antibody …

S Benvenuti, A Sartore-Bianchi, F Di Nicolantonio… - Cancer research, 2007 - AACR
S Benvenuti, A Sartore-Bianchi, F Di Nicolantonio, C Zanon, M Moroni, S Veronese, S Siena
Cancer research, 2007AACR
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 …
Abstract
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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