Selective inhibition of CDK9 in triple negative breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to its inherent tumor heterogeneity.
• TNBC tumors exhibit a dependency on transcription, making transcription regulators like cyclin-dependent kinase 9 (CDK9) potential therapeutic targets.

Purpose of the Study:

• To preclinically evaluate the efficacy and mechanism of a novel selective CDK9 inhibitor, named CDDD11-8, in triple-negative breast cancer models.

Main Methods:

• Utilized TNBC cell lines, patient-derived organoids, and patient-derived explant models for in vitro and ex vivo testing.
• Assessed proliferation inhibition, cell cycle arrest, apoptosis, and on-target CDK9 inhibition (RNAPII phosphorylation, MYC/MCL1 downregulation).
• Evaluated in vivo efficacy using TNBC xenograft models and assessed toxicity in mice and human breast tissues.

Main Results:

• CDDD11-8 demonstrated dose-dependent inhibition of proliferation and induced apoptosis across TNBC cell lines and patient-derived organoids (IC50 range: 272-771 nM).
• Confirmed on-target inhibition of CDK9, leading to reduced MYC and MCL1 oncogene expression and RNAPII pausing at gene promoters.
• Oral administration of CDDD11-8 effectively inhibited TNBC xenograft tumor growth in vivo without significant toxicity.

Conclusions:

• CDK9 represents a viable therapeutic target for triple-negative breast cancer.
• The novel selective CDK9 inhibitor CDDD11-8 exhibits significant preclinical efficacy in various TNBC models, including chemo-resistant and metastatic subtypes.
• CDDD11-8 shows potential as a safe and effective targeted therapy for TNBC.