Elevated ribosome biogenesis in oncogene‐driven cancers is commonly targeted by DNA‐damaging cytotoxic drugs. Our previous first‐in‐human trial of CX‐5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA polymerase I (Pol I) transcription, revealed single‐agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in the in vivo efficacy of CX‐5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here, we reveal the molecular basis for this improved efficacy observed in vivo, which is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this cotreatment is driven by translational rewiring that results in dysregulated cellular metabolism and induction of a cAMP‐dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies thus identify key molecular mechanisms underpinning the response of blood cancers to selective inhibition of ribosome biogenesis and define metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I‐directed therapies.

中文翻译：

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重新编程的mRNA翻译驱动对核糖体生物发生的治疗靶向的抗性。

在致癌基因驱动的癌症中，核糖体的生物合成升高通常是由破坏DNA的细胞毒性药物靶向的。我们之前的CX-15461首次人体试验（一种新型的，基因毒性较小的药物，可通过抑制RNA聚合酶I（Pol I）转录来特异性抑制核糖体的生物发生）显示了单药治疗难治性血液癌的功效。尽管有这种临床反应，患者仍无法治愈。同时，我们证明了PI3K / AKT / mTORC1途径抑制剂与CX-5461的体内功效显着改善。在这里，我们揭示了体内观察到的这种改善功效的分子基础，这与编码细胞代谢调节剂的mRNA的特异性抑制有关。重要的是，对这种协同治疗的获得性耐药是由翻译重排驱动的，翻译重排导致细胞代谢失调，并诱导了cAMP依赖性途径，这对包括淋巴瘤和急性髓性白血病在内的血液癌症的生存至关重要。因此，我们的研究确定了支持血液癌症对核糖体生物发生的选择性抑制的反应的关键分子机制，并定义了代谢脆弱性，这将有助于针对Pol I定向疗法的更有效方案的合理设计。