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 (Gly 12Val) 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2643-2648 |
| Number of pages | 6 |
| Journal | Cancer Research |
| Volume | 67 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Mar 15 2007 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. / Benvenuti, Silvia; Sartore-Bianchi, Andrea; Di Nicolantonio, Federica; Zanon, Carlo; Moroni, Mauro; Veronese, Silvio; Siena, Salvatore; Bardelli, Alberto.
In: Cancer Research, Vol. 67, No. 6, 15.03.2007, p. 2643-2648.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies
AU - Benvenuti, Silvia
AU - Sartore-Bianchi, Andrea
AU - Di Nicolantonio, Federica
AU - Zanon, Carlo
AU - Moroni, Mauro
AU - Veronese, Silvio
AU - Siena, Salvatore
AU - Bardelli, Alberto
PY - 2007/3/15
Y1 - 2007/3/15
N2 - 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 (Gly 12Val) 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.
AB - 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 (Gly 12Val) 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.
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U2 - 10.1158/0008-5472.CAN-06-4158
DO - 10.1158/0008-5472.CAN-06-4158
M3 - Article
VL - 67
SP - 2643
EP - 2648
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 6
ER -