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Sustained EGFR/Ras/MAPK signaling is associated with various cancers. Hence, blocking EGFR and its downstream effectors has become an established target in anti-cancer therapeutics. However, targeted agents face several challenges which limit their clinical use such as inter-patient variation, mutation, and resistance. Therefore, the identification of biomarkers that could predict the treatment outcome in cancer patients is crucial. Annexin A6 (AnxA6) is a calcium-dependent membrane binding protein with potential tumor suppressor properties. It was shown to bind and promote the involvement of p120GAP and protein kinase Cα (PKCα), two negative regulators of the EGFR/Ras/MAPK pathway, in the signal termination of this cascade. Increasing evidence points at the involvement of scaffold proteins, like AnxA6, in the sensitivity of cancer cells towards anti-cancer drugs. In this study, we examined the influence of single and combinatorial treatments targeting the EGFR/Ras/MAPK signaling cascade on the oncogenic proliferation of A431 cells in the presence and absence of AnxA6. Using A431wt cells, which lack endogenous AnxA6, and A431-A6 cells, a well characterized cell line which stably overexpress AnxA6, we investigated clonogenic growth in the presence of the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, the EGFR-targeted monoclonal antibody cetuximab, the MEK1/2 inhibitor PD98059, and the PKCα inhibitors BIM-I and Gö 6976 via clonogenic and MTS assays. We found that treating the cells with TKIs, MEK1/2 or PKCα inhibitors was able to effectively reduce colony and cell growth more than the individual drugs, and this inhibition was more pronounced in AnxA6 overexpressing cells. Furthermore, combinatorial treatment of A431 cancer cells with TKIs together with MEK1/2 inhibitors was more effective in cells expressing AnxA6. The data presented here suggest AnxA6 as a possible biomarker that could predict treatment outcome in EGFR-related cancers. |
