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  3. Targeting Wnt/β-catenin signaling enhances the efficacy of anti-CD38 immunotherapy in multiple myeloma

Targeting Wnt/β-catenin signaling enhances the efficacy of anti-CD38 immunotherapy in multiple myeloma

  • Neoplasia. 2025 Oct 23:70:101242. doi: 10.1016/j.neo.2025.101242.
Heng Li 1,  Yunguang Chen 2,  Michaela Gregorova 3,  Tingting Yang 4,  Xiayi Zhang 5,  Xiaoyu Yu 6,  Zhen Wang 7,  Haiying Hua 8,  Long Ye 9,  Xiaowei Qi 10,  Marcel Spaargaren 11,  Steven T Pals 12,  Zemin Ren 13
Affiliations

Affiliations

  • 1 Department of Basic Medical Sciences, Wuxi School of Medicine; Jiangnan University; Jiangnan University Medical Center, Wuxi, Jiangsu 214122, PR China. Electronic address: liheng_00@163.com.
  • 2 Department of Basic Medical Sciences, Wuxi School of Medicine; Jiangnan University; Jiangnan University Medical Center, Wuxi, Jiangsu 214122, PR China. Electronic address: chen1125631993@163.com.
  • 3 Department of Pathology, Amsterdam UMC location University of Amsterdam, Amsterdam 1105 AZ; Lymphoma and Myeloma Center Amsterdam - LYMMCARE; Cancer Center Amsterdam (CCA), The Netherlands. Electronic address: michaela.gregorova13@gmail.com.
  • 4 Department of Basic Medical Sciences, Wuxi School of Medicine; Jiangnan University; Jiangnan University Medical Center, Wuxi, Jiangsu 214122, PR China. Electronic address: tingtinyang@163.com.
  • 5 Department of Basic Medical Sciences, Wuxi School of Medicine; Jiangnan University; Jiangnan University Medical Center, Wuxi, Jiangsu 214122, PR China. Electronic address: 18108697229@163.com.
  • 6 Department of Basic Medical Sciences, Wuxi School of Medicine; Jiangnan University; Jiangnan University Medical Center, Wuxi, Jiangsu 214122, PR China. Electronic address: 8202210008@jiangnan.edu.cn.
  • 7 Department of Basic Medical Sciences, Wuxi School of Medicine; Jiangnan University; Jiangnan University Medical Center, Wuxi, Jiangsu 214122, PR China. Electronic address: zhenwang@jiangnan.edu.cn.
  • 8 Department of Hematology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu 214122, PR China. Electronic address: huahy007@163.com.
  • 9 Department of Hematology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu 214122, PR China. Electronic address: yelong@jiangnan.edu.cn.
  • 10 Department of Pathology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu 214122, PR China. Electronic address: qixiaowei97@163.com.
  • 11 Department of Pathology, Amsterdam UMC location University of Amsterdam, Amsterdam 1105 AZ; Lymphoma and Myeloma Center Amsterdam - LYMMCARE; Cancer Center Amsterdam (CCA), The Netherlands. Electronic address: marcel.spaargaren@amsterdamumc.nl.
  • 12 Department of Pathology, Amsterdam UMC location University of Amsterdam, Amsterdam 1105 AZ; Lymphoma and Myeloma Center Amsterdam - LYMMCARE; Cancer Center Amsterdam (CCA), The Netherlands. Electronic address: s.t.pals@amsterdamumc.nl.
  • 13 Department of Basic Medical Sciences, Wuxi School of Medicine; Jiangnan University; Jiangnan University Medical Center, Wuxi, Jiangsu 214122, PR China; Department of Pathology, Amsterdam UMC location University of Amsterdam, Amsterdam 1105 AZ; Lymphoma and Myeloma Center Amsterdam - LYMMCARE; Cancer Center Amsterdam (CCA), The Netherlands; Department of Hematology, Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, Jiangsu 214122, PR China. Electronic address: renzemin@jiangnan.edu.cn.
PMID: 41135362 DOI: 10.1016/j.neo.2025.101242
Abstract

Background: Previous studies have shown that the Wnt/β-catenin signaling pathway is aberrantly activated in multiple myeloma (MM) and regulates the growth of MM cells, while recent studies reported crosstalk between Wnt and STAT3 signaling in various non-MM systems. In addition, it has been shown that STAT3 regulates the expression of CD38, the key target of current antibody therapies in MM. Therefore, we aimed to investigate the impact of inhibiting the Wnt signaling on the efficacy of anti-CD38 immunotherapy.

Methods: We utilized dnTCF overexpression and β-catenin knockout to inhibit the Wnt signaling. Flow cytometry was used to analyze the expression of CD38. NK92MI-CD16 and CB-derived NK cells were used to conduct ADCC in cell lines and patient-derived MM. A xenograft mouse model was used to evaluate the therapeutic efficacy of inhibiting Wnt signaling in combination with daratumumab in vivo.

Results: We demonstrate that inhibition of Wnt signaling results in reduced STAT3 activity in both MM cell lines and primary MM samples. The suppression of STAT3 activity by Wnt signaling inhibition significantly enhances the expression of CD38, which is a crucial determinant of the clinical response to anti-CD38 treatment, viz. daratumumab. In accordance, targeting of Wnt signaling with the Wnt Inhibitor ICG-001 greatly enhanced the anti-MM efficacy of daratumumab in vitro as well as in an in vivo mouse model.

Conclusions: These findings demonstrated that targeting Wnt signaling enhances the efficacy of daratumumab and provide a strong rationale for combining daratumumab with Wnt-signaling inhibition as a therapeutic strategy in MM.

Keywords

CD38; Daratumumab; Multiple myeloma; STAT3 pathway; Wnt/β-catenin.

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