Nuclear EGFR is required for cisplatin resistance and DNA repair

The epidermal growth factor receptor (EGFR) has been shown to be able to translocate to the nucleus where it is involved in many cellular process including transcriptional regulation and DNA repair. Recently, it has been shown that the DNA damage-inducing agents ionizing radiation (IR) and cisplatin are able to induce EGFR nuclear localization, and this nuclear localization is correlated with increased DNA-PK activity, which plays an essential role in DNA double stranded repair. Here we sought to determine if there is a causal relationship between nuclear EGFR and DNA repair activity. We found that mutation in the nuclear localization signal (NLS) of EGFR (mNLS), known to be unable to translocate to the nucleus, released EGFR induced resistance to cisplatin. Re-introduction of an NLS in the C-terminal allowed EGFR to re-enter the nucleus and the cells regained resistance to cisplatin. In addition, we show that the re-expression of a functional nuclear localization sequence in EGFR (mNLS-R) is not only able to restore its resistance to cisplatin, but also reduced the DNA damage caused by cisplatin, and restored DNA repair activity. Thus, we demonstrate here that nuclear EGFR is required for DNA repair and resistance to cisplatin treatment.