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

作者：Montagut C^*; Iglesias M; Arumi M; Bellosillo B; Gallen M; Martinez Fernandez A; Martinez Aviles L; Canadas I; Dalmases A; Moragon E; Lema L; Serrano S; Rovira A; Rojo F; Bellmunt J; Albanell J

来源：British Journal of Cancer, 2010, 102(7): 1137-1144.

DOI：10.1038/sj.bjc.6605612

• MKP-1
• cetuximab
• CRC
• RAS
• molecular marker

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 (n = 3) had MKP-1 overexpression. Among KRAS wildtype 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).
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. British Journal of Cancer (2010) 102, 1137-1144. doi:10.1038/sj.bjc.6605612 www.bjcancer.

• 出版日期2010-3-30