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

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 identifcation of other biomarkers of response. On the basis of pre-clinical evidence, we hypothesised that mitogen-activated protein kinase phosphatase-I (MKP-I), 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-I expression as assessed by immunohistochemistry. RESULTS: As expected, clinical benefit was confined to wild-type KRAS and BRAF patients. Mitogen-activated protein kinase phosphatase-I 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- I overexpression. Among KRAS wild-type patients, MKP-I overexpressors had a 7% response rate (RR), whereas patients not overexpressing MKP-I had a 44% RR (P=0.03). Moreover, median time to progression was significantly longer in MKP-I non-overexpressing patients (32 vs 13 weeks, P = 0.009). CONCLUSION: These results support the concept of MKP-I as a promising negative marker of response to cetuximab-based treatment in CRC patients with wild-type KRAS.