Elsevier

Radiotherapy and Oncology

Volume 108, Issue 3, September 2013, Pages 370-377
Radiotherapy and Oncology

Review
Nuclear EGFR as a molecular target in cancer

https://doi.org/10.1016/j.radonc.2013.06.010Get rights and content

Abstract

The epidermal growth factor receptor (EGFR) has been one of the most targeted receptors in the field of oncology. While anti-EGFR inhibitors have demonstrated clinical success in specific cancers, most patients demonstrate either intrinsic or acquired resistance within one year of treatment. Many mechanisms of resistance to EGFR inhibitors have been identified, one of these being attributed to alternatively localized EGFR from the cell membrane into the cell’s nucleus. Inside the nucleus, EGFR functions as a co-transcription factor for several genes involved in cell proliferation and angiogenesis, and as a tyrosine kinase to activate and stabilize proliferating cell nuclear antigen and DNA dependent protein kinase. Nuclear localized EGFR is highly associated with disease progression, worse overall survival in numerous cancers, and enhanced resistance to radiation, chemotherapy, and the anti-EGFR therapies gefitinib and cetuximab. In this review the current knowledge of how nuclear EGFR enhances resistance to cancer therapeutics is discussed, in addition to highlighting ways to target nuclear EGFR as an anti-cancer strategy in the future.

Section snippets

The role of nuclear EGFR in resistance to cancer therapeutics

Intrinsic and acquired tumor cell resistance to both conventional and targeted cancer therapies remains one of the largest obstacles to overcome clinically. While nuclear EGFR is observed in cells of high proliferative origin, numerous reports describe increased nuclear localization of EGFR in models of cancer resistance to different therapeutic regimes [28], [29], [37], [38], [39]. These studies identified that nuclear EGFR could enhance resistance by influencing DNA damage repair, DNA

Future prospective of the nuclear RTK field

From the identification of nuclear localized EGFR in highly proliferative tissues to the uncovering of its vibrant roles in enhancing tumorigenic processes, the field of nuclear HER family receptors has blossomed over the past ten years. Even with the exposé of over 50 articles citing the presence and/or functions of nuclear EGFR in cancer, this field is still in its infancy. Studies have yet to show that nuclear EGFR functions as a true oncogene separate from its membrane-localized

Cell lines

The human HNSCC cell lines SCC1, SCC6, and SCC1483 were kindly supplied by Dr. T. Carey (University of Michigan, MI, USA) [75]. The human breast cancer cell lines SKBr3, MDAMB468, and SUM229 were kindly supplied by Dr. J. Boerner (Wayne State University School of Medicine, Karmanos Cancer Institute, MI, USA) [76]. The human MCF-7 and hamster CHOK1 cells were purchased from ATCC (Manassas, VA, USA). All cell lines were maintained in their respective media with 10% fetal bovine serum and 1%

Competing of interests

The authors declare no competing interests.

Authors’ contributions

TMB and DLW performed the literature search and drafted the manuscript. TMB and MI performed all experimentation depicted in this manuscript. All authors provided critical review of the manuscript and approved the final draft.

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