DYRK1A Is a Novel Regulator of TGFβ Signalling and Determines Sensitivity to OXPHOS Inhibition

Intervening in mitochondrial oxidative phosphorylation (OXPHOS) has emerged as a potential therapeutic strategy for certain types of cancers. However, the exploration of targeting OXPHOS for the treatment of liver cancer is still limited, and the regulatory network involved in OXPHOS inhibition remains largely unexplored. Here, employing kinome-based CRISPR screening, we find that OXPHOS inhibitor IACS-010759 exhibits limited effect in liver cancer cells due to the function of dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). Genetic inactivation or pharmacological inhibition of DYRK1A combined with OXPHOS inhibitors activates transforming growth factor β (TGFβ) signalling, which is crucial for OXPHOS inhibition-triggered cell death in liver cancer cells. Mechanistically, DYRK1A directly phosphorylates SMAD3 at Thr132, thereby suppressing the negative impact of TGFβ signalling on the transcription of the glutamine transporter solute carrier family 1 member 5 (SLC1A5). This mechanism compensates for the increased glutamine requirement (?) upon OXPHOS inhibition, leading to the resistance of liver cancer cells to OXPHOS inhibition. Finally, we validated the therapeutic efficacy of targeting OXPHOS in combination with DYRK1A inhibition in multiple liver cancer models in vivo. Our study identifies DYRK1A as a novel regulator of TGF β signalling and elucidates the regulatory mechanisms governing the response to OXPHOS inhibition in tumour cells, providing novel insights into targeting OXPHOS for liver cancer therapy.