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MUC1-C is a target in lenalidomide resistant multiple myeloma
Li Yin1, Ashujit Tagde1, Reddy Gali2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Abstract:
Lenalidomide (LEN) acts directly on multiple myeloma (MM) cells by inducing cereblon-mediated degradation of interferon regulatory factor 4, Ikaros (IKZF)1 and IKZF3, transcription factors that are essential for MM cell survival. The mucin 1 (MUC1) C-terminal transmembrane subunit (MUC1-C) oncoprotein is aberrantly expressed by MM cells and protects against reactive oxygen species (ROS)-mediated MM cell death. The present studies demonstrate that targeting MUC1-C with GO-203, a cell-penetrating peptide inhibitor of MUC1-C homodimerization, is more than additive with LEN in downregulating the WNT/β-catenin pathway, suppressing MYC, and inducing late apoptosis/necrosis. We show that the GO-203/LEN combination acts by synergistically increasing ROS and, in turn, suppressing β-catenin. LEN resistance has been linked to activation of the WNT/β-catenin→CD44 pathway. In this regard, our results further demonstrate that targeting MUC1-C is effective against LEN-resistant MM cells. Moreover, GO-203 resensitized LEN-resistant MM cells to LEN treatment in association with suppression of β-catenin and CD44. Targeting MUC1-C also resulted in downregulation of CD44 on the surface of primary MM cells. These findings, and the demonstration that expression of MUC1 and CD44 significantly correlate in microarrays from primary MM cells, provide support for combining GO-203 with LEN in the treatment of MM and in LEN-resistance.
Insights
Combining GO-203 with lenalidomide (LEN) shows promise for multiple myeloma (MM) treatment. This combination synergistically increases reactive oxygen species (ROS), overcoming lenalidomide resistance by targeting MUC1-C and the WNT/β-catenin pathway.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Lenalidomide (LEN) targets multiple myeloma (MM) cells via cereblon, degrading IKZF1/IKZF3 transcription factors essential for MM survival.
- Mucin 1 (MUC1) C-terminal subunit (MUC1-C) oncoprotein in MM cells confers resistance to reactive oxygen species (ROS)-mediated cell death.
Purpose of the Study:
- To investigate the efficacy of targeting MUC1-C with GO-203 in combination with LEN for MM treatment.
- To explore the mechanisms underlying the GO-203/LEN combination therapy, including its effect on ROS, WNT/β-catenin pathway, and lenalidomide resistance.
Main Methods:
- Utilized GO-203, a peptide inhibitor of MUC1-C homodimerization, in combination with LEN.
- Assessed the impact on WNT/β-catenin pathway, MYC suppression, apoptosis/necrosis, ROS levels, and CD44 expression in MM cells.
- Evaluated efficacy in both LEN-sensitive and LEN-resistant MM models, including primary MM cells.
Main Results:
- The GO-203/LEN combination demonstrated synergistic effects, surpassing additive outcomes in downregulating the WNT/β-catenin pathway and suppressing MYC.
- The combination therapy synergistically increased ROS, leading to suppressed β-catenin and induced late apoptosis/necrosis.
- GO-203 effectively targeted LEN-resistant MM cells, resensitizing them to LEN by suppressing β-catenin and CD44, and downregulated CD44 on primary MM cells.
Conclusions:
- Targeting MUC1-C with GO-203 is a viable strategy to enhance LEN efficacy in MM.
- The GO-203/LEN combination overcomes LEN resistance, potentially through synergistic ROS induction and β-catenin/CD44 pathway modulation.
- Combined targeting of MUC1-C and LEN holds significant therapeutic potential for MM, including in cases of lenalidomide resistance.
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