Implication of nuclear EGFR in the development of resistance to anticancer therapies

Epidermal growth factor receptor (EGFR) was identified as a major oncogenic factor in various types of cancer, and thereby has been considered as an attractive therapeutic target for cancer therapy. The well-characterized classic function of this plasma membrane-bound receptor is transduction of extracellular mitogenic signals to a variety of intracellular downstream signaling cascades associated with tumorigenesis. Aberrantly expressed EGFR also undergoes direct nuclear translocation to induce transcription of genes associated with cell proliferation, cell cycle regulation, and tumor progression. Emerging evidence suggests the existence of a new role of nuclear EGFR signaling in conferring acquired resistance in response to various anticancer therapies. In this review, we summarize the current understanding of how EGFR translocates into the nucleus in response to ionizing radiation, chemotherapy, and anti-EGFR target agents. The emerging impact of nuclear EGFR in modulating the cellular sensitivity of cancer cells to these anticancer treatments will also be discussed. A better understanding of the nuclear EGFR pathways in response to anticancer therapies will facilitate the development of novel strategies to overcome the acquired resistance.