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The EGFR-HER2 module: a stem cell approach to understanding a prime target and driver of solid tumors

Oncogene volume 35, pages 2949–2960 (2016)Cite this article

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Abstract

The epidermal growth factor receptor (EGFR) and a coreceptor denoted HER2/ERBB2 are frequently overexpressed or mutated in solid tumors, such as carcinomas and gliomas. In line with driver roles, cancer drugs intercepting EGFR or HER2 currently outnumber therapies targeting other hubs of signal transduction. To explain the roles for EGFR and HER2 as prime drivers and targets, we take lessons from invertebrates and refer to homeostatic regulation of several mammalian tissues. The model we infer ascribes to the EGFR-HER2 module pivotal functions in rapid clonal expansion of progenitors called transient amplifying cells (TACs). Accordingly, TACs of tumors suffer from replication stress, and hence accumulate mutations. In addition, several lines of evidence propose that in response to EGF and related mitogens, TACs might undergo dedifferentiation into tissue stem cells, which might enable entry of oncogenic mutations into the stem cell compartment. According to this view, antibodies or kinase inhibitors targeting EGFR-HER2 effectively retard some solid tumors because they arrest mutation-enriched TACs and possibly inhibit their dedifferentiation. Deeper understanding of the EGFR-HER2 module and relations between cancer stem cells and TACs will enhance our ability to control a broad spectrum of human malignancies.

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Acknowledgements

We thank Lilach Gilboa and Maik Dahlhoff for insightful discussions. MRS is supported by the German Research Foundation (DFG), the Else-Kröner-Fresenius Stiftung, the Fritz Thyssen Foundation and the Wilhelm Sander-Stiftung. YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. Currently, he is Research Professor of the Israel Cancer Research Fund. We would like to acknowledge financial support from the European Research Council, the Dr Miriam and Sheldon G Adelson Medical Research Foundation and the family of Mr Marvin Tanner.

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  1. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany

    M R Schneider

  2. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Y Yarden

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Schneider, M., Yarden, Y. The EGFR-HER2 module: a stem cell approach to understanding a prime target and driver of solid tumors. Oncogene 35, 2949–2960 (2016). https://doi.org/10.1038/onc.2015.372

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