Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Aberrant pre-mRNA splicing is a hallmark of many cancers, presenting a target for anti-neoplastic strategies.
• Cdc2-like kinases (CLKs) are crucial for exon recognition in the splicing machinery and are implicated in cancer development.

Purpose of the Study:

• To evaluate T-025, an orally available CLK inhibitor, as a potential anti-cancer therapeutic.
• To identify biomarkers predictive of T-025 sensitivity and elucidate its mechanism of action.

Main Methods:

• Treatment of cancer cells and animal models with T-025.
• Assessment of CLK-dependent phosphorylation, pre-mRNA splicing changes, cell death, and tumor growth.
• Correlation of CLK2 expression and MYC amplification with T-025 efficacy.

Main Results:

• T-025 effectively reduced CLK-dependent phosphorylation, inducing skipped exons, cell death, and growth suppression in vitro and in vivo.
• High CLK2 expression or MYC amplification were identified as biomarkers for T-025 sensitivity.
• MYC activation sensitized cancer cells to CLK inhibitors, leading to synergistic cell death.

Conclusions:

• T-025 is a potent CLK inhibitor with demonstrated in vivo anti-tumor efficacy in a MYC-driven breast cancer model.
• CLK inhibitors, like T-025, represent a promising therapeutic avenue for cancers with aberrant splicing, especially those driven by MYC.
• CLK2 expression and MYC amplification serve as valuable biomarkers for patient stratification in T-025 therapy.