Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer

Kyle Knickelbein, Jingshan Tong, Dongshi Chen, Yi Jun Wang, Sandra Misale, Alberto Bardelli, Jian Yu, Lin Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.

Original languageEnglish
Pages (from-to)4599-4610
Number of pages12
JournalOncogene
Volume37
Issue number33
DOIs
Publication statusPublished - Aug 16 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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