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

Oncogene
Kyle KnickelbeinLin Zhang

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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Citations

Dec 28, 2019·Journal of Cellular and Molecular Medicine·Liangjun LiWeiling Li
Mar 18, 2020·Journal of Cellular and Molecular Medicine·Shiqi KongYan Meng
Apr 12, 2020·Journal of Cellular and Molecular Medicine·Yingxiao CaoYanhui Qi
May 23, 2020·Journal of Cellular and Molecular Medicine·Yingxiao CaoYanhui Qi
Dec 7, 2018·Cancer Gene Therapy·Zhicheng YaoXin Jiang
May 23, 2019·Molecular and Cellular Biochemistry·Jiangning Li, Xiaofeng Li
Mar 29, 2020·Journal of Cellular and Molecular Medicine·Guangyong ChenHang Zhao
Jan 30, 2020·Journal of Cellular and Molecular Medicine·Xin LiYingxiao Cao
Jul 25, 2020·Cell Communication and Signaling : CCS·Hua YeLiao Cui
Mar 28, 2020·Molecular Carcinogenesis·Hang RuanJian Yu
Aug 28, 2019·Biochemical and Biophysical Research Communications·Heng Zhao, Ningji Gong

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Methods Mentioned

BETA
GTPase
flow cytometry
immunoprecipitation
transfection
PCR
electrophoresis
ChIP
xenograft

Software Mentioned

GraphPad Prism

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