Basal-A Triple-Negative Breast Cancer Cells Selectively Rely on RNA Splicing for Survival

Area of Science:

• Molecular oncology
• Cancer genetics
• Drug discovery

Background:

• Triple-negative breast cancer (TNBC), the most common subtype, has a poor prognosis.
• Identifying specific vulnerabilities in basal-like TNBC is crucial for developing targeted therapies.

Purpose of the Study:

• To identify shared and selective genetic vulnerabilities in basal-like TNBC.
• To evaluate the therapeutic potential of targeting RNA splicing and proteasome pathways in TNBC.

Main Methods:

• A directed siRNA lethality screen was conducted on 7 human breast cancer cell lines.
• Dependency genes, including those involved in RNA splicing (e.g., PRPF8, PRPF38A) and proteasome function, were analyzed.
• The effects of splicing modulator E7107 and proteasome inhibitor bortezomib were assessed in TNBC cell lines and xenografts.

Main Results:

• Thirty common dependency genes were identified, highlighting the importance of RNA splicing and proteasome genes.
• Knockdown of PRPF8 or PRPF38A, or treatment with E7107, caused widespread splicing alterations.
• E7107 treatment inhibited basal-A TNBC cell growth and xenograft progression, with enhanced efficacy when combined with bortezomib.

Conclusions:

• Targeting RNA splicing, particularly components of the U4/U6.U5 tri-snRNP complex, represents a viable strategy for basal-like TNBC.
• Combined inhibition of splicing and proteasome pathways demonstrates significant antitumor activity.
• This dual-targeting approach offers a promising new therapeutic avenue for patients with basal-like TNBC.