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Article

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

1
Translational Research Unit, Albacete University Hospital, 02008 Albacete, Spain
2
Centro Regional de Investigaciones Biomédicas (CRIB), Castilla-La Mancha University (UCLM), 02008 Albacete, Spain
3
Instituto de Biología Molecular y Celular del Cáncer, CSIC, IBSAL and CIBERONC, 37007 Salamanca, Spain
4
Faculty of Nursing, Castilla-La Mancha University (UCLM), 02008 Albacete, Spain
5
Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico San Carlos (HCSC),Instituto de Investigación Sanitaria (IdISSC) and CIBERONC, 28040 Madrid, Spain
6
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; https://doi.org/10.3390/ijms23105476
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. https://doi.org/10.3390/ijms23105476

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. https://doi.org/10.3390/ijms23105476

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. https://doi.org/10.3390/ijms23105476

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