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IL-6 Blockade Enhances the Efficacy of CDK4/6 Inhibitor in BRCA1-Mutant Triple-Negative Breast Cancer Cells
Li Pan1, Changyou Shi1, Joungil Choi2
1Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Abstract:
Breast cancer gene 1 (BRCA1) is a tumor suppressor gene essential for DNA repair, and its mutations are linked to aggressive breast cancers with poor prognosis. While poly (ADP-ribose) polymerase (PARP) inhibitors benefit some patients with BRCA1-mutant, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, issues such as limited efficacy and drug resistance persist. This is especially critical for triple-negative breast cancer (TNBC), which lacks targeted therapies. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors such as abemaciclib-FDA-approved for estrogen receptor (ER)-positive/HER2-negative breast cancer-are emerging as potential treatments for TNBC. We evaluated abemaciclib in BRCA1-mutant TNBC cell lines (SUM149, HCC1937, and MDA-MB-436) and found them to be sensitive to the drug. However, treatment induced cellular senescence and Interleukin-6 (IL-6) secretion, which may promote drug resistance. To address this, we inhibited IL-6 signaling using bazedoxifene or glycoprotein 130 (GP130) siRNA, and both of which enhanced abemaciclib sensitivity. Combination treatment with bazedoxifene and abemaciclib synergistically inhibited cell migration and invasion, and induced apoptosis. In a mammary fat pad TNBC tumor model, the combination treatment significantly suppressed SUM149 tumor growth more than either agent alone. These findings support co-targeting IL-6 and CDK4/6 as a novel therapeutic strategy for BRCA1-mutant TNBC.
Insights
Targeting Interleukin-6 (IL-6) with bazedoxifene enhances abemaciclib effectiveness in BRCA1-mutant triple-negative breast cancer (TNBC) by overcoming drug resistance and inhibiting tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- BRCA1 mutations are linked to aggressive breast cancers and poor prognosis.
- PARP inhibitors offer limited efficacy and face resistance in BRCA1-mutant cancers, especially triple-negative breast cancer (TNBC).
- CDK4/6 inhibitors like abemaciclib show promise for TNBC, but resistance mechanisms need addressing.
Purpose of the Study:
- To evaluate abemaciclib efficacy in BRCA1-mutant TNBC.
- To investigate abemaciclib-induced resistance mechanisms involving Interleukin-6 (IL-6).
- To explore combination therapy targeting CDK4/6 and IL-6 signaling for improved TNBC treatment.
Main Methods:
- Assessed abemaciclib sensitivity in BRCA1-mutant TNBC cell lines.
- Investigated abemaciclib-induced IL-6 secretion and its role in resistance.
- Utilized bazedoxifene or GP130 siRNA to inhibit IL-6 signaling.
- Evaluated combination therapy effects on cell migration, invasion, apoptosis, and in vivo tumor growth.
Main Results:
- Abemaciclib treatment induced cellular senescence and IL-6 secretion in BRCA1-mutant TNBC cells.
- Inhibiting IL-6 signaling with bazedoxifene or GP130 siRNA enhanced abemaciclib sensitivity.
- Combination therapy synergistically reduced cell migration and invasion, and induced apoptosis.
- Combined bazedoxifene and abemaciclib significantly suppressed tumor growth in a TNBC mouse model.
Conclusions:
- Co-targeting IL-6 and CDK4/6 represents a promising therapeutic strategy for BRCA1-mutant TNBC.
- Overcoming abemaciclib resistance through IL-6 pathway inhibition is feasible.
- Combination therapy demonstrates enhanced efficacy in preclinical models of TNBC.
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