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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
STAT3 inhibition eradicates multiple myeloma stem-like cells and induces immunogenic cell death
Yuqian Sha1,2, Wenyu Li1,2, Yan Zhang1
1Blood Disease Institute, Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical University, Xuzhou, China.
Abstract:
Signal transducer and activator of transcription 3 (STAT3) is a pivotal oncogenic driver in multiple myeloma (MM), and its constitutive activation promotes malignant plasma cell proliferation, survival, and drug resistance in the bone marrow microenvironment. Despite therapeutic advances, MM remains incurable due to persistent STAT3-driven tumorigenesis and the resilience of MM stem cells. We investigated the therapeutic potential of napabucasin (BBI608), a novel STAT3 inhibitor, in MM. Our data demonstrated that BBI608 potently suppressed MM cell proliferation in vitro and in vivo, while significantly impairing the clonogenic potential and inducing robust apoptosis. Mechanistically, BBI608 exhibited dual efficacy by targeting bulk tumor cells and eradicating the stem-like compartment of MM cells, thereby addressing a critical therapeutic challenge. Moreover, we revealed that BBI608 triggered immunogenic cell death (ICD) via the activation of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which subsequently enhanced T-cell-mediated anti-tumor immunity. Our findings highlight STAT3 inhibition as a promising strategy to simultaneously eradicate MM cells, target stem cell reservoirs, and harness anti-tumor immunity, providing a robust rationale for the clinical translation of BBI608 in MM therapy.
Insights
Napabucasin (BBI608), a novel STAT3 inhibitor, effectively targets multiple myeloma (MM) cells and stem cells. This STAT3 inhibition induces immunogenic cell death, enhancing anti-tumor immunity for potential MM therapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Signal transducer and activator of transcription 3 (STAT3) is a key driver in multiple myeloma (MM), promoting cancer cell growth and drug resistance.
- Current MM therapies face challenges due to persistent STAT3 activation and resilient MM stem cells, limiting cures.
Purpose of the Study:
- To investigate the therapeutic potential of napabucasin (BBI608), a novel STAT3 inhibitor, for treating multiple myeloma (MM).
- To evaluate BBI608's efficacy in targeting both bulk MM tumor cells and MM stem cells.
- To explore BBI608's mechanism of action, including its effect on immunogenic cell death and anti-tumor immunity.
Main Methods:
- In vitro and in vivo studies using MM cell lines and models.
- Assessment of MM cell proliferation, clonogenic potential, and apoptosis.
- Analysis of endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and T-cell activation.
Main Results:
- BBI608 demonstrated potent suppression of MM cell proliferation and clonogenic potential, inducing significant apoptosis.
- BBI608 effectively targeted both bulk MM cells and the stem-like cell compartment.
- BBI608 triggered immunogenic cell death (ICD) by activating ER stress and UPR, enhancing T-cell-mediated anti-tumor immunity.
Conclusions:
- STAT3 inhibition with BBI608 presents a promising strategy for MM treatment.
- BBI608 simultaneously eradicates MM cells, targets stem cell reservoirs, and harnesses anti-tumor immunity.
- These findings provide a strong rationale for the clinical development of BBI608 in MM therapy.
