Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
Institute of Pediatrics, Children's Hospital of Fudan University, 201102 Shanghai, China.
Proc Natl Acad Sci U S A. 2021 Jan 5;118(1). doi: 10.1073/pnas.2020102118. Epub 2020 Dec 21.
The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and an attractive anticancer target that integrates diverse signals to control cell proliferation. Previous studies using mTOR inhibitors have shown that mTOR targeting suppresses gene expression and cell proliferation. To date, however, mTOR-targeted therapies in cancer have seen limited efficacy, and one key issue is related to the development of evasive resistance. In this manuscript, through the use of a gene targeting mouse model, we have found that inducible deletion of in hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to the loss, HSCs increase chromatin accessibility and activate global gene expression, contrary to the effects of short-term inhibition by mTOR inhibitors. Mechanistically, such genomic changes are due to a rewiring and adaptive activation of the ERK/MNK/eIF4E signaling pathway that enhances the protein translation of RNA polymerase II, which in turn leads to increased gene expression, allowing the HSCs to thrive despite the loss of a functional mTOR pathway. This adaptive mechanism can also be utilized by leukemia cells undergoing long-term mTOR inhibitor treatment to confer resistance to mTOR drug targeting. The resistance can be counteracted by MNK, CDK9, or c-Myc inhibition. These results provide insights into the physiological role of mTOR in mammalian stem cell regulation and implicate a mechanism of evasive resistance in the context of mTOR targeting.
雷帕霉素的靶蛋白（mTOR）是细胞生长的核心调节剂，也是一种有吸引力的抗癌靶点，它整合了多种信号来控制细胞增殖。之前使用 mTOR 抑制剂的研究表明，mTOR 靶向抑制可抑制基因表达和细胞增殖。然而，迄今为止，癌症的 mTOR 靶向治疗效果有限，一个关键问题与逃避性耐药的发展有关。在本手稿中，通过使用基因靶向小鼠模型，我们发现诱导性敲除造血干细胞（HSCs）中的 会导致静止期损失和增殖增加。为了适应 的缺失， HSCs 增加染色质可及性并激活全局基因表达，这与 mTOR 抑制剂的短期抑制作用相反。从机制上讲，这种基因组变化是由于 ERK/MNK/eIF4E 信号通路的重新布线和适应性激活，从而增强了 RNA 聚合酶 II 的蛋白质翻译，这反过来又导致 基因表达增加，使 HSCs 能够在失去功能性 mTOR 途径的情况下茁壮成长。这种适应性机制也可被经历长期 mTOR 抑制剂治疗的白血病细胞利用，从而赋予它们对 mTOR 药物靶向的耐药性。可以通过 MNK、CDK9 或 c-Myc 抑制来抵抗这种耐药性。这些结果提供了对 mTOR 在哺乳动物干细胞调控中的生理作用的深入了解，并暗示了在 mTOR 靶向治疗中逃避耐药的机制。
