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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...

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Autores principales: Yang, Cuixia, Sheng, Yumeng, Shi, Xiaoxing, Liu, Yiwen, He, Yiqing, Du, Yan, Zhang, Guoliang, Gao, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
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.
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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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