DYRK1A-TGFβ Signaling Axis Determines Sensitivity to OXPHOS Inhibition in Hepatocellular Carcinoma

Intervening in mitochondrial OXPHOS has emerged as a potential therapeutic strategy for certain types of cancers. Employing kinome-based CRISPR screen, we find that knockout of DYRK1A synergizes with OXPHOS inhibitor IACS-010759 in liver cancer cells. Targeting DYRK1A combined with OXPHOS inhibitors activates TGFβ signaling, which is crucial for OXPHOS inhibition-triggered cell death. Mechanistically, upregulation of glutamine transporter SLC1A5 transcription compensates for the increased glutamine requirement upon OXPHOS inhibition. DYRK1A directly phosphorylates SMAD3 Thr132, thereby suppressing the negative impact of TGFβ signaling on transcription of SLC1A5, leading to intrinsic resistance of liver cancer cells to OXPHOS inhibition. Moreover, we demonstrate the therapeutic efficacy of IACS-010759 in combination with DYRK1A inhibition in multiple liver cancer models, including xenograftes, patient-derived xenograftes and spontaneous tumor model. Our study elucidates how the DYRK1A-TGFβ signaling axis controls the response of tumor cells to OXPHOS inhibition and provides valuable insights into targeting OXPHOS for liver cancer therapy.