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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Change history
16 May 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41388-023-02682-x
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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.
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Knickelbein, K., Tong, J., Chen, D. et al. Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. Oncogene 37, 4599–4610 (2018). https://doi.org/10.1038/s41388-018-0289-x
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DOI: https://doi.org/10.1038/s41388-018-0289-x
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