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 journalArticle

5 Citations (Scopus)

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

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Anti-Idiotypic Antibodies
Colorectal Neoplasms
Aurora Kinases
Oncogenes
Transcriptional Activation
Therapeutics
Apoptosis
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. / Knickelbein, Kyle; Tong, Jingshan; Chen, Dongshi; Wang, Yi Jun; Misale, Sandra; Bardelli, Alberto; Yu, Jian; Zhang, Lin.

In: Oncogene, Vol. 37, No. 33, 16.08.2018, p. 4599-4610.

Research output: Contribution to journalArticle

Knickelbein, K, Tong, J, Chen, D, Wang, YJ, Misale, S, Bardelli, A, Yu, J & Zhang, L 2018, 'Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer', Oncogene, vol. 37, no. 33, pp. 4599-4610. https://doi.org/10.1038/s41388-018-0289-x
Knickelbein, Kyle ; Tong, Jingshan ; Chen, Dongshi ; Wang, Yi Jun ; Misale, Sandra ; Bardelli, Alberto ; Yu, Jian ; Zhang, Lin. / Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. In: Oncogene. 2018 ; Vol. 37, No. 33. pp. 4599-4610.
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AU - Bardelli, Alberto

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