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Oncogene. 2018 Aug;37(33):4599-4610. doi: 10.1038/s41388-018-0289-x. Epub 2018 May 14.

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

Author information

1
UMPC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
2
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
3
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer, New York, 10065, NY, USA.
4
Candiolo Cancer Institute-FPO, IRCCS, Candiolo (TO), 10060, Italy.
5
Department of Oncology, University of Torino, Candiolo (TO), 10060, Italy.
6
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
7
UMPC Hillman Cancer Center, Pittsburgh, PA, 15213, USA. zhanglx@upmc.edu.
8
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. zhanglx@upmc.edu.

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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