Quantitative proteomics analysis identifies MUC1 as an effect sensor of EGFR inhibition

Abstract

Tumor responses to cancer therapeutics are generally monitored every 2–3 months based on changes in tumor size. Dynamic biomarkers that reflect effective engagement of targeted therapeutics to the targeted pathway, so-called “effect sensors”, would fulfill a need for non-invasive, drug-specific indicators of early treatment effect. Using a proteomics approach to identify effect sensors, we demonstrated MUC1 upregulation in response to epidermal growth factor receptor (EGFR)-targeting treatments in breast and lung cancer models. To achieve this, using semi-quantitative mass spectrometry, we found MUC1 to be significantly and durably upregulated in response to erlotinib, an EGFR-targeting treatment. MUC1 upregulation was regulated transcriptionally, involving PI3K-signaling and STAT3. We validated these results in erlotinib-sensitive human breast and non-small lung cancer cell lines. Importantly, erlotinib treatment of mice bearing SUM149 xenografts resulted in increased MUC1 shedding into plasma. Analysis of MUC1 using serial blood sampling may therefore be a new, relatively non-invasive tool to monitor early and drug-specific effects of EGFR-targeting therapeutics.

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Acknowledgements

We thank members of the Medical Oncology Department and Cancer Research Center Groningen for helpful discussions. This work is financially supported by the European Research Council (ERC-Advanced Grant ERC-2011-293-445 to E.G.E.d.V.). E.G.E.d.V. and M.A.T.M.v.V. conceived the study. H.R.d.B., E.J., S.v.C., and M.E. designed and performed in vitro experiments. E.J. and F.F. performed MS experiments and analysis. R.S.N.F. and H.R.d.B. performed pathway analysis. M.P., D.F.S., and W.H. designed and manufactured molecular imaging tools. H.R.d.B. and M.P. performed in vivo experiments. H.R.d.B., E.G.E.d.V., and M.A.T.M.v.V. wrote the manuscript and all authors contributed to editing of the manuscript. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository 51 with the dataset identifier PXD005985.

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Correspondence to Marcel A. T. M. van Vugt.

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de Boer, H.R., Pool, M., Joosten, E. et al. Quantitative proteomics analysis identifies MUC1 as an effect sensor of EGFR inhibition. Oncogene 38, 1477–1488 (2019). https://doi.org/10.1038/s41388-018-0522-7

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