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Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer
Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the cell cycle and transcriptional regulation. In this article, we explore the antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound against CDK9. Breast cancer cell lines from different subtypes wer...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9146359/ https://www.ncbi.nlm.nih.gov/pubmed/35628286 http://dx.doi.org/10.3390/ijms23105476 |
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author | Noblejas-López, María del Mar Gandullo-Sánchez, Lucía Galán-Moya, Eva M. López-Rosa, Raquel Tébar-García, David Nieto-Jiménez, Cristina Gómez-Juárez, Mónica Burgos, Miguel Pandiella, Atanasio Ocaña, Alberto |
author_facet | Noblejas-López, María del Mar Gandullo-Sánchez, Lucía Galán-Moya, Eva M. López-Rosa, Raquel Tébar-García, David Nieto-Jiménez, Cristina Gómez-Juárez, Mónica Burgos, Miguel Pandiella, Atanasio Ocaña, Alberto |
author_sort | Noblejas-López, María del Mar |
collection | PubMed |
description | Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the cell cycle and transcriptional regulation. In this article, we explore the antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound against CDK9. Breast cancer cell lines from different subtypes were used. Transcriptomic mapping of CDKs in breast cancer demonstrated that the expression of CDK9 predicted a detrimental outcome in basal-like tumors (HR = 1.51, CI = 1.08–2.11, p = 0.015) and, particularly, in the luminal B subtype with HER2+ expression (HR = 1.82, CI = 1.17–2.82, p = 0.0069). The novel CDK9 PROTAC, THAL-SNS-032, displayed a profound inhibitory activity in MCF7, T47D, and BT474 cells, with less effect in SKBR3, HCC1569, HCC1954, MDA-MB-231, HS578T, and BT549 cells. The three cell lines with HER2 overexpression and no presence of ER, SKBR3, HCC1569, and HCC1954 displayed an EC50 three times higher compared to ER-positive and dual ER/HER2-positive cell lines. BT474-derived trastuzumab-resistant cell lines displayed a particular sensitivity to THAL-SNS-032. Western blot analyses showed that THAL-SNS-032 caused a decrease in CDK9 levels in BT474, BT474-RH, and BT474-TDM1R cells, and a significant increase in apoptosis. Experiments in animals demonstrated an inverse therapeutic index of THAL-SNS-032, with doses in the nontherapeutic and toxic range. The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors. |
format | Online Article Text |
id | pubmed-9146359 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91463592022-05-29 Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer Noblejas-López, María del Mar Gandullo-Sánchez, Lucía Galán-Moya, Eva M. López-Rosa, Raquel Tébar-García, David Nieto-Jiménez, Cristina Gómez-Juárez, Mónica Burgos, Miguel Pandiella, Atanasio Ocaña, Alberto Int J Mol Sci Article Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the cell cycle and transcriptional regulation. In this article, we explore the antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound against CDK9. Breast cancer cell lines from different subtypes were used. Transcriptomic mapping of CDKs in breast cancer demonstrated that the expression of CDK9 predicted a detrimental outcome in basal-like tumors (HR = 1.51, CI = 1.08–2.11, p = 0.015) and, particularly, in the luminal B subtype with HER2+ expression (HR = 1.82, CI = 1.17–2.82, p = 0.0069). The novel CDK9 PROTAC, THAL-SNS-032, displayed a profound inhibitory activity in MCF7, T47D, and BT474 cells, with less effect in SKBR3, HCC1569, HCC1954, MDA-MB-231, HS578T, and BT549 cells. The three cell lines with HER2 overexpression and no presence of ER, SKBR3, HCC1569, and HCC1954 displayed an EC50 three times higher compared to ER-positive and dual ER/HER2-positive cell lines. BT474-derived trastuzumab-resistant cell lines displayed a particular sensitivity to THAL-SNS-032. Western blot analyses showed that THAL-SNS-032 caused a decrease in CDK9 levels in BT474, BT474-RH, and BT474-TDM1R cells, and a significant increase in apoptosis. Experiments in animals demonstrated an inverse therapeutic index of THAL-SNS-032, with doses in the nontherapeutic and toxic range. The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors. MDPI 2022-05-13 /pmc/articles/PMC9146359/ /pubmed/35628286 http://dx.doi.org/10.3390/ijms23105476 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Noblejas-López, María del Mar Gandullo-Sánchez, Lucía Galán-Moya, Eva M. López-Rosa, Raquel Tébar-García, David Nieto-Jiménez, Cristina Gómez-Juárez, Mónica Burgos, Miguel Pandiella, Atanasio Ocaña, Alberto Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer |
title | Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer |
title_full | Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer |
title_fullStr | Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer |
title_full_unstemmed | Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer |
title_short | Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer |
title_sort | antitumoral activity of a cdk9 protac compound in her2-positive breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9146359/ https://www.ncbi.nlm.nih.gov/pubmed/35628286 http://dx.doi.org/10.3390/ijms23105476 |
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