Format

Send to

Choose Destination
See comment in PubMed Commons below
Cancer Res. 2011 Nov 15;71(22):7071-9. doi: 10.1158/0008-5472.CAN-11-0128. Epub 2011 Nov 8.

p53 modulates acquired resistance to EGFR inhibitors and radiation.

Author information

1
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.

Abstract

There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor-resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor-resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation.

PMID:
22068033
PMCID:
PMC3229180
DOI:
10.1158/0008-5472.CAN-11-0128
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center