The authors demonstrate that adaptive as well as acquired resistance to the EGFR inhibitor serlotinib, a TKI of EGFR, converged on MAPK activation
The authors demonstrate that adaptive as well as acquired resistance to the EGFR inhibitor serlotinib, a TKI of EGFR, converged on MAPK activation.38 The rationale of combining the ErbB family inhibitor Afatinib with MEK inhibitor PD-901 has been recently demonstrated by Lin et al. Results ERK1/2 phosphorylation was rebounded by prolonged cetuximab administration and was induced by fractionated IR, which could be suppressed by a MEK inhibitor as a radiosensitiser. In silico assessments suggested that EGFR-MAPK cascade genes and proteins could predict HNSCC patients p-Synephrine survival as a prognostic signature. Conclusions Activation of ERK1/2 signalling contributes to the cellular defence of HNSCC against cetuximab and fractionated IR treatment. EGFR-MAPK axis has a prognostic significance in HNSCC. web tool.28 A heat map representation of the protein expression values was made by supervised clustering with test. Correlation analysis was performed by Spearmans rho. Overall survival (OS) was calculated using the KaplanCMeier method and compared by the Log-Rank test. web tool and two clusters with an either low or high prognostic risk were defined by PI and Cox fitting (Fig.?4b). With the exception of MAPK1, differential expression of all other genes was highly significant between the high-risk as compared to the low-risk group (Fig.?4c). As expected, MAP2K2 transcript levels were downregulated in the Rabbit Polyclonal to CRMP-2 high-risk groups. Furthermore, KaplanCMeier plot and Log-Rank analysis revealed a significant difference in overall survival between the high and low risk group (Fig.?4d; Hazard ratio [HR]?=?1.91, confidence interval [CI]?=?1.37C2.64). This finding was confirmed in the two independent cohorts (Fig.?S1). In summary, these findings demonstrated that a gene expression signature related to the EGFR-MEK-ERK pathway predicts the clinical outcome for HNSCC patients. Open in a separate window Fig. 4 Prognostic analysis of EGFR-MEK-ERK gene signature in HNSCC by TCGA database.a Visualisation of a correlation matrix for EGFR-MEK-ERK pathway gene expression values. Positive correlations were shown in blue and negative correlations in red. Only correlation test. d Overall survival of risk groups was evaluated by KaplanCMeier survival plot and Log-Rank test. Total number of patients at risk were displayed at indicated time points. The predictive value of EGFR-MEK-ERK gene p-Synephrine signature for survival is confirmed on protein level To confirm the prognostic value of the gene signature related to EGFR-MEK-ERK pathway on the protein level, we analysed the proteomic dataset from TCPA-HNSCC. Spearmans correlation analysis was applied to evaluate the association among EGFR-MEK-ERK signalling components, including EGFR, pEGFR(Tyr1068), pEGFR(Tyr1173), MEK1, pMEK1, ERK2, pERK1/2. Our data show that pEGFR(Tyr1173) is positively correlated with levels of MEK and ERK phosphorylation, while phospho-EGFR(Tyr1068) revealed a strong positive correlation with EGFR, MEK1, ERK2 protein levels, and a significantly negative relationship with levels of MEK phosphorylation (Fig.?5a). Heatmap clusters indicated different groups with low or high prognostic risk, as described previously (Fig.?5b). Differential protein expression analysis confirmed our TMA data that pEGFR(Tyr1173) were significantly elevated in the high-risk groups as compared to the low-risk p-Synephrine groups. In addition, EGFR, pEGFR(Tyr1068), pMEK1 were significantly induced in the high-risk groups as compared to the risk groups (Fig.?5c). KaplanCMeier survival analysis of HNSCC cohort based on protein expression has validated the findings from the genomic dataset, which suggests EGFR-MEK-ERK cascade proteins could predict HNSCC patient survival as a prognostic signature (Fig.?5d). Open in a separate window Fig. 5 Prognostic analysis of EGFR-MEK-ERK proteins expression in HNSCC by TCGA database.a Visualisation of a correlation matrix for EGFR-MEK-ERK pathway protein expression values. Positive correlations were shown in blue and negative correlations in red. Only correlation test. d Overall survival of risk groups was evaluated by KaplanCMeier survival plot and Log-Rank test. Total number of patients at risk were displayed at indicated time points. Discussion Cetuximab is.