DYRK1A-TGF-β signaling axis determines sensitivity to OXPHOS inhibition in hepatocellular carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic target in cancer.
• Understanding resistance mechanisms to OXPHOS inhibitors is crucial for effective liver cancer treatment.

Purpose of the Study:

• To identify genetic modifiers that synergize with OXPHOS inhibition in liver cancer.
• To elucidate the molecular mechanisms underlying the interplay between DYRK1A, TGF-β signaling, and OXPHOS inhibition resistance.

Main Methods:

• Kinome-based CRISPR screening was employed to identify synergistic targets.
• Experiments involved liver cancer cell lines, molecular signaling assays, and in vivo tumor models (xenografts, patient-derived xenografts, spontaneous models).
• Specific assays included Western blotting for protein phosphorylation (SMAD3 Thr132) and gene expression analysis for SLC1A5.

Main Results:

• Knockout of DYRK1A synergizes with the OXPHOS inhibitor IACS-010759 in liver cancer cells.
• Combined targeting of DYRK1A and OXPHOS activates TGF-β signaling, promoting cell death.
• DYRK1A directly phosphorylates SMAD3, suppressing TGF-β's negative regulation of SLC1A5 transcription, thus overcoming resistance to OXPHOS inhibition.
• Therapeutic efficacy of the combination was confirmed in multiple preclinical liver cancer models.

Conclusions:

• The DYRK1A-TGF-β signaling axis is a key regulator of liver cancer cell response to OXPHOS inhibition.
• Targeting DYRK1A in combination with OXPHOS inhibitors represents a promising therapeutic strategy for liver cancer.
• This study provides critical insights into overcoming intrinsic resistance to OXPHOS-targeted therapies.