Mitogen-activated protein kinase phosphatase-1 (MKP-1) impairs the response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab in metastatic colorectal cancer patients

C. Montagut, M. Iglesias, M. Arumi, B. Bellosillo, M. Gallen, A. Martinez-Fernandez, L. Martinez-Aviles, I. Cãadas, A. Dalmases, E. Moragon, L. Lema, S. Serrano, A. Rovira, F. Rojo, J. Bellmunt, J. Albanell

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19 Citations (Scopus)

Abstract

Background:The validation of KRAS mutations as a negative marker of response to anti-epidermal growth factor receptor (EGFR) antibodies has meant a seminal advance towards treatment individualisation of colorectal cancer (CRC) patients. However, as a KRAS wild-type status does not guarantee a response to anti-EGFR antibodies, a current challenge is the identification of other biomarkers of response. On the basis of pre-clinical evidence, we hypothesised that mitogen-activated protein kinase phosphatase-1 (MKP-1), a phosphatase that inactivates MAPKs, could be a mediator of resistance to anti-EGFR antibodies.Methods:Tumour specimens from 48 metastatic CRC patients treated with cetuximab-based chemotherapy were evaluated for KRAS and BRAF mutational status and MKP-1 expression as assessed by immunohistochemistry.Results:As expected, clinical benefit was confined to wild-type KRAS and BRAF patients. Mitogen-activated protein kinase phosphatase-1 was overexpressed in 16 patients (33%) and was not associated with patient baseline clinicopathological characteristics and KRAS mutational status. All patients with BRAF mutations (n3) had MKP-1 overexpression. Among KRAS wild-type patients, MKP-1 overexpressors had a 7% response rate (RR), whereas patients not overexpressing MKP-1 had a 44% RR (P0.03). Moreover, median time to progression was significantly longer in MKP-1 non-overexpressing patients (32 vs 13 weeks, P0.009).Conclusion:These results support the concept of MKP-1 as a promising negative marker of response to cetuximab-based treatment in CRC patients with wild-type KRAS. © 2010 Cancer Research UK All rights reserved.
Original languageEnglish
Pages (from-to)1137-1144
JournalBritish Journal of Cancer
Volume102
Issue number7
DOIs
Publication statusPublished - 1 Mar 2010

Keywords

  • Cetuximab
  • CRC
  • MKP-1
  • Molecular marker
  • RAS

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