MUC1-C dependence in treatment-resistant prostate cancer uncovers a target for antibody-drug conjugate therapy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Prostate cancer (PC), castration-resistant PC (CRPC), and neuroendocrine PC (NEPC) often develop resistance to therapies.
• Aberrant expression of mucin 1 (MUC1) is linked to poor outcomes in CRPC/NEPC.
• The role of the oncogenic MUC1-C protein in driving treatment resistance remains unclear.

Purpose of the Study:

• To investigate whether the MUC1-C protein drives treatment resistance in various forms of prostate cancer.
• To elucidate the mechanisms by which MUC1-C confers resistance, focusing on cancer stem cell (CSC) properties.
• To evaluate the therapeutic potential of targeting MUC1-C using an M1C antibody-drug conjugate (ADC).

Main Methods:

• Assessed MUC1-C's necessity for resistance in PC cells to enzalutamide (ENZ) and in CRPC/NEPC cells to docetaxel (DTX).
• Investigated MUC1-C's role in upregulating aerobic glycolysis and suppressing reactive oxygen species (ROS) in resistant cells.
• Evaluated the efficacy of an M1C ADC in suppressing drug-resistant CRPC/NEPC CSC self-renewal and tumor xenograft growth.

Main Results:

• MUC1-C is essential for resistance to ENZ in PC and DTX in CRPC/NEPC.
• MUC1-C confers resistance by increasing aerobic glycolysis and decreasing ROS, supporting the CSC state.
• An M1C ADC effectively inhibited CSC self-renewal and reduced tumor growth in xenograft models, including patient-derived refractory NEPC.

Conclusions:

• MUC1-C drives treatment resistance in advanced prostate cancers, including CRPC and NEPC, by maintaining the cancer stem cell phenotype.
• Targeting MUC1-C with an M1C ADC presents a promising therapeutic strategy for overcoming treatment resistance in these aggressive prostate cancer subtypes.