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Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence

SIMPLE SUMMARY: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used to treat metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Despite the effectiveness of CDK4/6 inhibitors, acquired resistance occurs in almost all cases. Strategie...

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Autores principales: Pandey, Kamal, Park, Nahee, Park, Kyung-Soon, Hur, Jin, Cho, Yong Bin, Kang, Minsil, An, Hee-Jung, Kim, Sewha, Hwang, Sohyun, Moon, Yong Wha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768442/
https://www.ncbi.nlm.nih.gov/pubmed/33260316
http://dx.doi.org/10.3390/cancers12123566
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author Pandey, Kamal
Park, Nahee
Park, Kyung-Soon
Hur, Jin
Cho, Yong Bin
Kang, Minsil
An, Hee-Jung
Kim, Sewha
Hwang, Sohyun
Moon, Yong Wha
author_facet Pandey, Kamal
Park, Nahee
Park, Kyung-Soon
Hur, Jin
Cho, Yong Bin
Kang, Minsil
An, Hee-Jung
Kim, Sewha
Hwang, Sohyun
Moon, Yong Wha
author_sort Pandey, Kamal
collection PubMed
description SIMPLE SUMMARY: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used to treat metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Despite the effectiveness of CDK4/6 inhibitors, acquired resistance occurs in almost all cases. Strategies to address this issue have not been developed yet. We investigated mechanisms of resistance to CDK4/6 inhibitor in breast cancer and potential therapeutic strategies. We found that cyclin E-CDK2 mediated phosphorylation of C-MYC is responsible for resistance to CDK4/6 inhibitor by suppressing C-MYC induced senescence. On the contrary, the synergistic anti-proliferative effect of the combined inhibition of CDK2 and CDK4/6 overcomes acquired resistance to CDK4/6 inhibitors by enhancing senescence. Our findings could pave the way for the development CDK2-specific kinase inhibitor for the treatment of breast cancers that are resistant to CDK4/6 inhibitor. ABSTRACT: Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor.
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spelling pubmed-77684422020-12-29 Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence Pandey, Kamal Park, Nahee Park, Kyung-Soon Hur, Jin Cho, Yong Bin Kang, Minsil An, Hee-Jung Kim, Sewha Hwang, Sohyun Moon, Yong Wha Cancers (Basel) Article SIMPLE SUMMARY: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used to treat metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Despite the effectiveness of CDK4/6 inhibitors, acquired resistance occurs in almost all cases. Strategies to address this issue have not been developed yet. We investigated mechanisms of resistance to CDK4/6 inhibitor in breast cancer and potential therapeutic strategies. We found that cyclin E-CDK2 mediated phosphorylation of C-MYC is responsible for resistance to CDK4/6 inhibitor by suppressing C-MYC induced senescence. On the contrary, the synergistic anti-proliferative effect of the combined inhibition of CDK2 and CDK4/6 overcomes acquired resistance to CDK4/6 inhibitors by enhancing senescence. Our findings could pave the way for the development CDK2-specific kinase inhibitor for the treatment of breast cancers that are resistant to CDK4/6 inhibitor. ABSTRACT: Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor. MDPI 2020-11-29 /pmc/articles/PMC7768442/ /pubmed/33260316 http://dx.doi.org/10.3390/cancers12123566 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pandey, Kamal
Park, Nahee
Park, Kyung-Soon
Hur, Jin
Cho, Yong Bin
Kang, Minsil
An, Hee-Jung
Kim, Sewha
Hwang, Sohyun
Moon, Yong Wha
Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence
title Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence
title_full Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence
title_fullStr Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence
title_full_unstemmed Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence
title_short Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence
title_sort combined cdk2 and cdk4/6 inhibition overcomes palbociclib resistance in breast cancer by enhancing senescence
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768442/
https://www.ncbi.nlm.nih.gov/pubmed/33260316
http://dx.doi.org/10.3390/cancers12123566
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