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.

靶向线粒体氧化磷酸化（mitochondrial Oxidative Phosphorylation, OXPHOS）已成为部分癌症的潜在治疗策略。本研究采用基于激酶组的CRISPR筛选，发现DYRK1A基因敲除可与氧化磷酸化抑制剂IACS-010759在肝癌细胞中产生协同效应。联合靶向DYRK1A与氧化磷酸化抑制剂可激活转化生长因子β（Transforming Growth Factor-β, TGF-β）信号通路，该通路对于氧化磷酸化抑制诱导的细胞死亡至关重要。从机制上而言，氧化磷酸化抑制会使细胞谷氨酰胺需求升高，谷氨酰胺转运体SLC1A5的转录上调可代偿这一增加的谷氨酰胺需求。DYRK1A可直接磷酸化SMAD3蛋白的Thr132位点，进而抑制TGF-β信号通路对SLC1A5转录的负调控作用，最终使肝癌细胞对氧化磷酸化抑制产生内在耐药性。此外，本研究在多种肝癌模型（包括异种移植瘤模型、患者来源异种移植瘤模型及自发肿瘤模型）中验证了IACS-010759联合DYRK1A抑制剂的治疗效果。本研究阐明了DYRK1A-TGF-β信号轴如何调控肿瘤细胞对氧化磷酸化抑制的应答，为靶向氧化磷酸化的肝癌治疗提供了极具价值的理论参考。