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Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer
María Del Mar Noblejas-López1,2, Lucía Gandullo-Sánchez3, Eva M Galán-Moya1,2,4
1Translational Research Unit, Albacete University Hospital, 02008 Albacete, Spain.
Abstract:
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.
Insights
A novel proteolysis-targeting chimera (PROTAC) compound targeting CDK9 shows potent anti-cancer activity in breast cancer cell lines. However, toxicity in animal models limits its use without targeted delivery, especially for HER2-positive and resistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinases (CDKs) regulate cell cycle and transcription.
- CDK9 expression correlates with poor prognosis in basal-like and HER2+ luminal B breast cancers.
- Proteolysis-targeting chimeras (PROTACs) offer a novel therapeutic strategy by degrading target proteins.
Purpose of the Study:
- To evaluate the antitumoral activity of a novel CDK9 PROTAC, THAL-SNS-032, against various breast cancer subtypes.
- To investigate the efficacy of THAL-SNS-032 in trastuzumab-resistant breast cancer models.
- To assess the safety and therapeutic index of THAL-SNS-032 in preclinical animal studies.
Main Methods:
- In vitro studies using multiple breast cancer cell lines representing different subtypes.
- Transcriptomic analysis of CDK expression in breast cancer.
- Western blot analysis to assess protein level changes and apoptosis.
- In vivo experiments in animal models to evaluate efficacy and toxicity.
Main Results:
- THAL-SNS-032 demonstrated potent inhibition in ER-positive and dual ER/HER2-positive cell lines, with higher EC50 in HER2-overexpressing, ER-negative lines.
- The compound showed particular sensitivity in trastuzumab-resistant BT474-derived cell lines, reducing CDK9 levels and increasing apoptosis.
- Animal studies revealed an inverse therapeutic index, with toxicity primarily in the gastrointestinal epithelium due to on-target, off-tumor effects.
Conclusions:
- The CDK9 PROTAC THAL-SNS-032 exhibits potent antitumoral properties against specific breast cancer subtypes, including resistant ones.
- On-target, off-tumor toxicity in the gastrointestinal tract necessitates targeted delivery strategies for clinical application.
- This PROTAC holds promise for treating ER/HER2-positive and HER2-resistant breast cancers if delivery can be specifically directed to tumor cells.
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