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Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer
Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by 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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195818/ https://www.ncbi.nlm.nih.gov/pubmed/29755130 http://dx.doi.org/10.1038/s41388-018-0289-x |
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author | Knickelbein, Kyle Tong, Jingshan Chen, Dongshi Wang, Yi-Jun Misale, Sandra Bardelli, Alberto Yu, Jian Zhang, Lin |
author_facet | Knickelbein, Kyle Tong, Jingshan Chen, Dongshi Wang, Yi-Jun Misale, Sandra Bardelli, Alberto Yu, Jian Zhang, Lin |
author_sort | Knickelbein, Kyle |
collection | PubMed |
description | Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by 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. |
format | Online Article Text |
id | pubmed-6195818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-61958182018-11-14 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 Oncogene Article Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by 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. 2018-05-14 2018-08 /pmc/articles/PMC6195818/ /pubmed/29755130 http://dx.doi.org/10.1038/s41388-018-0289-x Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article 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 |
title | Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer |
title_full | Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer |
title_fullStr | Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer |
title_full_unstemmed | Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer |
title_short | Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer |
title_sort | restoring puma induction overcomes kras-mediated resistance to anti-egfr antibodies in colorectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195818/ https://www.ncbi.nlm.nih.gov/pubmed/29755130 http://dx.doi.org/10.1038/s41388-018-0289-x |
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