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

Oncogenevolume 37pages45994610 (2018) | Download Citation

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.

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Acknowledgements

The authors thank our lab members for critical reading. This work is supported by U.S. National Institute of Health grants (R01CA106348, R01CA172136, R01CA203028, and R01CA217141 to LZ; U19AI068021 and R01CA215481 to JY). KK was supported by a fellowship from the Cotswold Foundation and the Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine. This project used the UPMC Hillman Cancer Center shared facilities that were supported in part by award P30CA047904.

Author information

Affiliations

  1. UMPC Hillman Cancer Center, Pittsburgh, PA, 15213, USA

    • Kyle Knickelbein
    • , Jingshan Tong
    • , Dongshi Chen
    • , Yi-Jun Wang
    • , Jian Yu
    •  & Lin Zhang
  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    • Kyle Knickelbein
    • , Jingshan Tong
    • , Dongshi Chen
    • , Yi-Jun Wang
    •  & Lin Zhang
  3. Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer, New York, 10065, NY, USA

    • Sandra Misale
  4. Candiolo Cancer Institute-FPO, IRCCS, Candiolo (TO), 10060, Italy

    • Alberto Bardelli
  5. Department of Oncology, University of Torino, Candiolo (TO), 10060, Italy

    • Alberto Bardelli
  6. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    • Jian Yu

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The authors declare that they have no conflict of interest.

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Correspondence to Lin Zhang.

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https://doi.org/10.1038/s41388-018-0289-x