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The quest to overcome resistance to EGFR-targeted therapies in cancer

Abstract

All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance.

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Figure 1: EGFR signaling pathways.
Figure 2: Timeline of key discoveries in the EGFR field.
Figure 3: Clinically validated resistance mechanisms to EGFR inhibitors.
Figure 4: Efficacy of targeted therapies in cancer treatment.

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Acknowledgements

This study is supported by US National Institutes of Health grants RO1CA114465 (P.A.J.), R01CA135257 (P.A.J.) and P01CA154303 (P.A.J.) and by an American Society of Clinical Oncology Young Investigator Award (C.R.C.).

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Correspondence to Pasi A Jänne.

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P.A.J. has received consulting fees from Astra-Zeneca, Boehringer Ingelheim, Clovis Oncology and Pfizer. P.A.J. also receives after-marketing royalties from Dana-Farber Cancer Institute on owned intellectual property regarding EGFR mutations.

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Chong, C., Jänne, P. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 19, 1389–1400 (2013). https://doi.org/10.1038/nm.3388

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