Mitogen-activated protein kinase phosphatase-1 (MKP-1) as a biomarker of resistance to cetuximab in colorectal cancer patients.

Abstract

e14018 Background: The validation of KRAS mutations as a negative marker of response to the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab has meant a seminal advance towards treatment individualization of colorectal cancer (CRC) patients. However, since KRAS wild-type status does not guarantee response to anti-EGFR antibodies, identification of other biomarkers of response is urgently needed. We hypothesized that MKP-1, a phosphatase that inactivates phospho-MAPKs including the EGFR downstream protein ERK, could be a mediator of resistance to anti-EGFR antibodies. Methods: Tumor specimens from 48 metastatic CRC patients treated with cetuximab-based chemotherapy were evaluated for KRAS and BRAF mutational status as well as MKP-1 expression as assessed by immunohistochemistry. Results: As expected, clinical benefit was confined to wild-type KRAS and BRAF patients. MKP-1 was overexpressed in 16 patients (33%) and was not associated with patient baseline clinical characteristics or 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 while patients non- overexpressing MKP-1 had a 44% response rate (p = 0.03). Moreover median time to progression was significantly longer in MKP-1 non-overexpressing patients (32 vs. 13 weeks, p = 0.009). Conclusions: These results support the concept of MKP-1 as a promising marker of resistance to cetuximab-based treatment in colorectal cancer patients with KRAS wild-type status. No significant financial relationships to disclose.