Menin serves both tumor suppressor and promoter roles in a highly tumor-specific manner. In colorectal cancer, menin is overexpressed and plays a critical role in regulating transcription of SKP2, and combined treatment with a menin inhibitor and small-molecule EGFR inhibitor (EGFRi) leads to synergistic killing of colorectal cancer cells. However, the full spectrum of menin function in colorectal cancer remains uncertain. Herein, we demonstrate that menin inhibition increases glycolysis in colorectal cancer cells. This menin inhibitor–induced increase in glycolysis occurs in an mTOR-independent manner and enhances the sensitivity of colorectal cancer cells to EGFRis. In addition, we show that EGFRis induce autophagy in colorectal cancer cells, which is important for cell survival in the setting of combined treatment with an EGFRi and menin inhibitor. Inhibition of autophagy with chloroquine further sensitizes colorectal cancers to treatment with the combination of an EGFRi and menin inhibitor. Together, these findings uncover a novel role for menin in colorectal cancer as a repressor of glycolysis and demonstrate that menin inhibitor–induced increases in glycolysis sensitize colorectal cancer cells to EGFRis. In addition, these findings illustrate the importance of autophagy as a protective mechanism against EGFRis, especially in the presence of menin inhibition. Ultimately, these data open the possibility of using menin-mediated regulation of glycolysis to potentially improve treatment modalities for colorectal cancer.

中文翻译：

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Menin 介导的糖酵解抑制与自噬相结合可保护结肠癌免受小分子 EGFR 抑制剂的侵害


Menin 以高度肿瘤特异性的方式发挥肿瘤抑制和促进作用。在结直肠癌中，menin过度表达并在调节SKP2转录中发挥关键作用，menin抑制剂和小分子EGFR抑制剂（EGFRi）联合治疗可协同杀死结直肠癌细胞。然而，结直肠癌中 menin 的全部功能仍不确定。在此，我们证明 menin 抑制会增加结直肠癌细胞中的糖酵解。这种 menin 抑制剂诱导的糖酵解增加以不依赖 mTOR 的方式发生，并增强结直肠癌细胞对 EGFRis 的敏感性。此外，我们还发现 EGFRi 会诱导结直肠癌细胞自噬，这对于 EGFRi 和 menin 抑制剂联合治疗中的细胞存活非常重要。用氯喹抑制自噬进一步使结直肠癌对 EGFRi 和 menin 抑制剂的联合治疗敏感。总之，这些发现揭示了 menin 在结直肠癌中作为糖酵解抑制剂的新作用，并证明 menin 抑制剂诱导的糖酵解增加使结直肠癌细胞对 EGFRis 敏感。此外，这些发现说明了自噬作为针对 EGFRis 的保护机制的重要性，特别是在 menin 抑制存在的情况下。最终，这些数据开启了利用 menin 介导的糖酵解调节来潜在改善结直肠癌治疗方式的可能性。