Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784716544727580672
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
work_keys_str_mv AT noblejaslopezmariadelmar antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer
AT gandullosanchezlucia antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer
AT galanmoyaevam antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer
AT lopezrosaraquel antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer
AT tebargarciadavid antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer
AT nietojimenezcristina antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer
AT gomezjuarezmonica antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer
AT burgosmiguel antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer
AT pandiellaatanasio antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer
AT ocanaalberto antitumoralactivityofacdk9protaccompoundinher2positivebreastcancer