MUC1-C is a target in lenalidomide resistant multiple myeloma

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.