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

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 (n ¼ 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 ¼ 0.03). Moreover, median time to progression was significantly longer in MKP-1 non-overexpressing patients (32 vs 13 weeks, P ¼ 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.

FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer

“…Figure 1B is consistent with this hypothesis since cetuximab leads to activation of p38 and JNK. In agreement with this explanation, Montagut et al (2010) demonstrated in 2010 that MKP-1 overexpression impairs the response to cetuximab in mCRC patients. Our interpretation could be that overexpression of MKP-1 inhibits p38 activity and then prevent cetuximab maximal effect.…”

DUSP1 Phosphatase Regulates the Proinflammatory Milieu in Head and Neck Squamous Cell Carcinoma

“…In light of cytokine and chemokine findings discussed above, implications of these studies may extend well beyond HNSCC, as DUSP1 expression has been shown to be dysregulated in other cancers, such as breast, and may be predictive of response to targeted therapies, such as cetuximab (7,17). Genomic studies have not identified a common mutation or deletion, but a recent DNA methylation screen identified significantly increased promoter hypermethylation in over 80% of oral cancer tissues (18).…”

Interferon/STAT1 and neuregulin signaling pathways are exploratory biomarkers of cetuximab (Erbitux�) efficacy in KRAS wild-type squamous carcinomas: A pathway-based analysis of whole human-genome microarray data from cetuximab-adapted tumor cell-line models

“…Indeed, DUSP4 and DUSP6 were originally identified as top resistance markers to cetuximab in unselected patients and the use of a four-gene expression model, including AREG, EREG and DUSP6 (as well as SLC26A3 -solute carrier family 26 member 3) has been shown to improve the identification of responders among pre-selected KRAS WT mCRC (9,11). Recently, Montagut et al have revealed that DUSP4 protein can be considered a promising negative marker of response to cetuximab-based treatment in mCRC with WT KRAS (17). When they assessed DUSP4 expression by immunohistochemistry in a small series of mCRC patients, overexpression of DUSP4 protein significantly associated with lower response rates and shorter median time to progression among KRAS WT patients (17).…”

“…Recently, Montagut et al have revealed that DUSP4 protein can be considered a promising negative marker of response to cetuximab-based treatment in mCRC with WT KRAS (17). When they assessed DUSP4 expression by immunohistochemistry in a small series of mCRC patients, overexpression of DUSP4 protein significantly associated with lower response rates and shorter median time to progression among KRAS WT patients (17).…”