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Therapeutics, Targets, and Chemical Biology

p53 Modulates Acquired Resistance to EGFR Inhibitors and Radiation

Shyhmin Huang, Sergio Benavente, Eric A. Armstrong, Chunrong Li, Deric L. Wheeler and Paul M. Harari
Shyhmin Huang
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Sergio Benavente
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Eric A. Armstrong
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Chunrong Li
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Deric L. Wheeler
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Paul M. Harari
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DOI: 10.1158/0008-5472.CAN-11-0128
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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. Cancer Res; 71(22); 1–9. ©2011 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received January 18, 2011.
  • Revision received August 22, 2011.
  • Accepted September 11, 2011.
  • ©2011 American Association for Cancer Research.
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Published OnlineFirst November 8, 2011
doi: 10.1158/0008-5472.CAN-11-0128

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p53 Modulates Acquired Resistance to EGFR Inhibitors and Radiation
Shyhmin Huang, Sergio Benavente, Eric A. Armstrong, Chunrong Li, Deric L. Wheeler and Paul M. Harari
Cancer Res November 8 2011 DOI: 10.1158/0008-5472.CAN-11-0128

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p53 Modulates Acquired Resistance to EGFR Inhibitors and Radiation
Shyhmin Huang, Sergio Benavente, Eric A. Armstrong, Chunrong Li, Deric L. Wheeler and Paul M. Harari
Cancer Res November 8 2011 DOI: 10.1158/0008-5472.CAN-11-0128
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Cancer Research Online ISSN: 1538-7445
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