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CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor
Most luminal breast carcinomas (BrCas) bearing PIK3CA mutations initially respond to phosphoinositide-3-kinase (PI3K)-α inhibitors, but many eventually become resistant. The underlying mechanisms of this resistance remain obscure. In this work, we showed that a CD44(high) state due to aberrant isofo...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538592/ https://www.ncbi.nlm.nih.gov/pubmed/33024087 http://dx.doi.org/10.1038/s41419-020-03037-0 |
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author | Yang, Cuixia Sheng, Yumeng Shi, Xiaoxing Liu, Yiwen He, Yiqing Du, Yan Zhang, Guoliang Gao, Feng |
author_facet | Yang, Cuixia Sheng, Yumeng Shi, Xiaoxing Liu, Yiwen He, Yiqing Du, Yan Zhang, Guoliang Gao, Feng |
author_sort | Yang, Cuixia |
collection | PubMed |
description | Most luminal breast carcinomas (BrCas) bearing PIK3CA mutations initially respond to phosphoinositide-3-kinase (PI3K)-α inhibitors, but many eventually become resistant. The underlying mechanisms of this resistance remain obscure. In this work, we showed that a CD44(high) state due to aberrant isoform splicing was acquired from adaptive resistance to a PI3Kα inhibitor (BLY719) in luminal BrCas. Notably, the expression of CD44 was positively correlated with estrogen receptor (ER) activity in PIK3CA-mutant breast cancers, and ER-dependent transcription upon PI3Kα pathway inhibition was in turn mediated by CD44. Furthermore, the interaction of CD44 with the ligand hyaluronan (HA) initiated the Src-ERK signaling cascade, which subsequently maintained AKT and mTOR activity in the presence of a PI3Kα inhibitor. Activation of this pathway was prevented by disruption of the CD44/HA interaction, which in turn restored sensitivity to BLY719. Our results revealed that an ER-CD44-HA signaling circuit that mediates robust compensatory activation of the Src-ERK signaling cascade may contribute to the development of acquired resistance to PI3Kα inhibitors. This study provides new insight into the mechanism of adaptive resistance to PI3Kα inhibition therapy. |
format | Online Article Text |
id | pubmed-7538592 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75385922020-10-19 CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor Yang, Cuixia Sheng, Yumeng Shi, Xiaoxing Liu, Yiwen He, Yiqing Du, Yan Zhang, Guoliang Gao, Feng Cell Death Dis Article Most luminal breast carcinomas (BrCas) bearing PIK3CA mutations initially respond to phosphoinositide-3-kinase (PI3K)-α inhibitors, but many eventually become resistant. The underlying mechanisms of this resistance remain obscure. In this work, we showed that a CD44(high) state due to aberrant isoform splicing was acquired from adaptive resistance to a PI3Kα inhibitor (BLY719) in luminal BrCas. Notably, the expression of CD44 was positively correlated with estrogen receptor (ER) activity in PIK3CA-mutant breast cancers, and ER-dependent transcription upon PI3Kα pathway inhibition was in turn mediated by CD44. Furthermore, the interaction of CD44 with the ligand hyaluronan (HA) initiated the Src-ERK signaling cascade, which subsequently maintained AKT and mTOR activity in the presence of a PI3Kα inhibitor. Activation of this pathway was prevented by disruption of the CD44/HA interaction, which in turn restored sensitivity to BLY719. Our results revealed that an ER-CD44-HA signaling circuit that mediates robust compensatory activation of the Src-ERK signaling cascade may contribute to the development of acquired resistance to PI3Kα inhibitors. This study provides new insight into the mechanism of adaptive resistance to PI3Kα inhibition therapy. Nature Publishing Group UK 2020-10-06 /pmc/articles/PMC7538592/ /pubmed/33024087 http://dx.doi.org/10.1038/s41419-020-03037-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Yang, Cuixia Sheng, Yumeng Shi, Xiaoxing Liu, Yiwen He, Yiqing Du, Yan Zhang, Guoliang Gao, Feng CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor |
title | CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor |
title_full | CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor |
title_fullStr | CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor |
title_full_unstemmed | CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor |
title_short | CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor |
title_sort | cd44/ha signaling mediates acquired resistance to a pi3kα inhibitor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538592/ https://www.ncbi.nlm.nih.gov/pubmed/33024087 http://dx.doi.org/10.1038/s41419-020-03037-0 |
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