Interferon-Driven Biomarkers and Synergistic Therapy for PRMT5 Inhibition in Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to heterogeneous responses to targeted agents like PRMT5 inhibitors.
• Identifying reliable biomarkers for PRMT5 inhibitor sensitivity is crucial for effective TNBC treatment strategies.

Purpose of the Study:

• To identify biomarkers predicting response to PRMT5 inhibition in TNBC.
• To develop a combination therapy strategy to overcome resistance to PRMT5 inhibitors in TNBC.

Main Methods:

• Transcriptomic profiling of TNBC models treated with PRMT5 inhibitors.
• Assessing DNA damage and interferon (IFN) signaling pathways.
• Pre-clinical validation using patient-derived organoids (PDOs) and xenografts (PDXs).

Main Results:

• Basal interferon (IFN) signaling emerged as a predictive biomarker for PRMT5 inhibitor sensitivity in TNBC.
• Elevated DNA damage correlated with enhanced IFN pathway activity in sensitive TNBC models.
• Combining PARP inhibitor Olaparib with PRMT5 inhibitors demonstrated synergistic antitumor efficacy and overcame resistance in pre-clinical models.
• This combination therapy modulated the tumor microenvironment, improving anti-tumor immunity.

Conclusions:

• IFN-driven transcriptional signatures serve as predictive biomarkers for PRMT5 inhibitor response in TNBC.
• A combination strategy involving PRMT5 and PARP inhibitors offers a promising approach to enhance treatment efficacy and overcome resistance in TNBC.
• The dual targeting strategy promotes anti-tumor immunity, suggesting potential for durable responses.