TAK-981 potentiates doxorubicin immunocide in triple-negative breast cancer by IFN I-dependent NK cell stimulation
Jia Liu1, Yiming Wang2,3, Xiaoxia Wei1
1Department of Pharmacy, Shengli Clinical Medical, College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Pharmacy, Fujian Medical University, Fuzhou, 350001, P. R. China.
Objective:
This study aimed to investigate the synergistic antitumor effects and immunoregulatory functions of the SUMOylation inhibitor TAK-981 in combination with the chemotherapeutic agent doxorubicin (DOX) in triple-negative breast cancer (TNBC), as well as to evaluate the safety of this combination strategy, particularly its mitigating effect on DOX-induced cardiotoxicity.
Methods:
In vitro experiments were conducted to assess the effects of TAK-981 and DOX, both alone and in combination, on the type I interferon (IFN I) signaling pathway, cell proliferation, and apoptosis in TNBC cells. Mechanistic studies were performed to explore their impact on the IFN I/JAK1/STAT1 axis and the expression of the downstream NKG2D ligand NKG2DL (ULBP2). In vivo animal models were used to evaluate the antitumor efficacy of the combination therapy, its effect on natural killer (NK) cell activity, systemic toxicity, with a focus on its cardioprotective effects.
Results:
TAK-981 activated IFN I signaling, and DOX further enhanced IFN I pathway activity. The two drugs demonstrated a synergistic effect, significantly inducing apoptosis and inhibiting proliferation in TNBC cells. Mechanistically, the TAK-981 and DOX combination targeted the IFN I/JAK1/STAT1 signaling axis, downregulating the expression of the NKG2D ligand (ULBP2) through suppression of the NF-κB pathway. In vivo experiments confirmed that the combination therapy effectively inhibited tumor growth, enhanced NK cell activity, and did not increase systemic toxicity. Notably, TAK-981 significantly alleviated DOX-induced cardiotoxicity, improved cardiac function, and reduced fibrosis.
Conclusion:
The combination of an immunomodulatory agent with chemotherapy represents a novel therapeutic strategy for TNBC. TAK-981 not only synergizes with DOX to produce antitumor immun effects but also significantly mitigates DOX-induced cardiotoxicity, offering a promising new direction for improving the efficacy and safety of TNBC treatment.
Insights
The SUMOylation inhibitor TAK-981 combined with doxorubicin (DOX) shows synergistic antitumor effects in triple-negative breast cancer (TNBC). This combination also reduces doxorubicin-induced cardiotoxicity, improving treatment safety.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) remains a challenging malignancy with limited therapeutic options.
- Doxorubicin (DOX) is a chemotherapy agent with known cardiotoxicity, limiting its clinical use.
- SUMOylation inhibitors represent a novel class of therapeutic agents with potential immunomodulatory effects.
Purpose of the Study:
- To investigate the synergistic antitumor effects of TAK-981 and DOX in TNBC.
- To explore the immunoregulatory functions and mechanisms of this combination therapy.
- To evaluate the safety of the combination, focusing on mitigating DOX-induced cardiotoxicity.
Main Methods:
- In vitro studies assessed effects on type I interferon (IFN I) signaling, proliferation, and apoptosis in TNBC cells.
- Mechanistic studies explored the IFN I/JAK1/STAT1 axis and NKG2D ligand (ULBP2) expression.
- In vivo models evaluated antitumor efficacy, NK cell activity, systemic toxicity, and cardioprotective effects.
Main Results:
- TAK-981 and DOX synergistically inhibited TNBC cell proliferation and induced apoptosis.
- The combination activated IFN I signaling and targeted the IFN I/JAK1/STAT1/NF-κB pathway.
- In vivo, the therapy enhanced NK cell activity, reduced tumor growth, and significantly alleviated DOX-induced cardiotoxicity.
Conclusions:
- Combining the immunomodulatory agent TAK-981 with chemotherapy (DOX) is a promising strategy for TNBC.
- This combination demonstrates synergistic antitumor activity and enhances immunomodulation.
- TAK-981 significantly mitigates DOX-induced cardiotoxicity, improving the therapeutic index for TNBC treatment.
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