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.

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 (n=3) 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 (P=0.03). Moreover, median time to progression was significantly longer in MKP−1 non−overexpressing patients (32 vs 13 weeks, P=0.009).

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.

British Journal of Cancer advance online publication, 16 March 2010; doi:10.1038/sj.bjc.6605612 www.bjcancer.com.

PMID: 20234366 [PubMed − as supplied by publisher] Source: National Library of Medicine.