Next Article in Journal
Toll-like Receptor Response to Hepatitis C Virus Infection: A Recent Overview
Previous Article in Journal
Tryptophan in Nutrition and Health
Previous Article in Special Issue
Optimization of Short RNA Aptamers for TNBC Cell Targeting

This is an early access version, the complete PDF, HTML, and XML versions will be available soon.


Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer

Translational Research Unit, Albacete University Hospital, 02008 Albacete, Spain
Centro Regional de Investigaciones Biomédicas (CRIB), Castilla-La Mancha University (UCLM), 02008 Albacete, Spain
Instituto de Biología Molecular y Celular del Cáncer, CSIC, IBSAL and CIBERONC, 37007 Salamanca, Spain
Faculty of Nursing, Castilla-La Mancha University (UCLM), 02008 Albacete, Spain
Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico San Carlos (HCSC),Instituto de Investigación Sanitaria (IdISSC) and CIBERONC, 28040 Madrid, Spain
Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain
Author to whom correspondence should be addressed.
Academic Editor: Antonella Zannetti
Int. J. Mol. Sci. 2022, 23(10), 5476;
Received: 14 April 2022 / Revised: 10 May 2022 / Accepted: 12 May 2022 / Published: 13 May 2022
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.
Keywords: cyclin-dependent kinases; CDK9; HER2+ breast cancer; PROTACs; THAL-SNS-032 cyclin-dependent kinases; CDK9; HER2+ breast cancer; PROTACs; THAL-SNS-032
MDPI and ACS Style

Noblejas-López, M.d.M.; Gandullo-Sánchez, L.; Galán-Moya, E.M.; López-Rosa, R.; Tébar-García, D.; Nieto-Jiménez, C.; Gómez-Juárez, M.; Burgos, M.; Pandiella, A.; Ocaña, A. Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer. Int. J. Mol. Sci. 2022, 23, 5476.

AMA Style

Noblejas-López MdM, Gandullo-Sánchez L, Galán-Moya EM, López-Rosa R, Tébar-García D, Nieto-Jiménez C, Gómez-Juárez M, Burgos M, Pandiella A, Ocaña A. Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer. International Journal of Molecular Sciences. 2022; 23(10):5476.

Chicago/Turabian Style

Noblejas-López, María d.M., Lucía Gandullo-Sánchez, Eva M. Galán-Moya, Raquel López-Rosa, David Tébar-García, Cristina Nieto-Jiménez, Mónica Gómez-Juárez, Miguel Burgos, Atanasio Pandiella, and Alberto Ocaña. 2022. "Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer" International Journal of Molecular Sciences 23, no. 10: 5476.

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Back to TopTop