Watanabe Motoki, Boku Shogen, Kobayashi Kaito, Kurumida Yoichi, Sukeno Mamiko, Masuda Mitsuharu, Mizushima Katsura, Kato Chikage, Iizumi Yosuke, Hirota Kiichi, Naito Yuji, Mutoh Michihiro, Kameda Tomoshi, Sakai Toshiyuki
Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, 602-8566 Kyoto, Japan.
Cancer Treatment Center, Kansai Medical University Hospital, 573-1010 Osaka, Japan.
PNAS Nexus. 2022 May 16;1(2):pgac059. doi: 10.1093/pnasnexus/pgac059. eCollection 2022 May.
MEK inhibitors are among the most successful molecularly targeted agents used as cancer therapeutics. However, to treat cancer more efficiently, resistance to MEK inhibitor-induced cell death must be overcome. Although previous genetic approaches based on comprehensive gene expression analysis or RNAi libraries led to the discovery of factors involved in intrinsic resistance to MEK inhibitors, a feasible combined treatment with the MEK inhibitor has not yet been developed. Here, we show that a chemoproteoinformatics approach identifies ligands overcoming the resistance to cell death induced by MEK inhibition as well as the target molecule conferring this resistance. First, we used natural products, perillyl alcohol and sesaminol, which induced cell death in combination with the MEK inhibitor trametinib, as chemical probes, and identified ribosomal protein S5 (RPS5) as their common target protein. Consistently, trametinib induced cell death in RPS5-depleted cancer cells via upregulation of the apoptotic proteins BIM and PUMA. Using molecular docking and molecular dynamics (MD) simulations, we then screened FDA- and EMA-approved drugs for RPS5-binding ligands and found that acetylsalicylic acid (ASA, also known as aspirin) directly bound to RPS5, resulting in upregulation of BIM and PUMA and induction of cell death in combination with trametinib. Our chemoproteoinformatics approach demonstrates that RPS5 confers resistance to MEK inhibitor-induced cell death, and that aspirin could be repurposed to sensitize cells to MEK inhibition by binding to RPS5.
MEK抑制剂是用作癌症治疗药物的最成功的分子靶向药物之一。然而，为了更有效地治疗癌症，必须克服对MEK抑制剂诱导的细胞死亡的抗性。尽管先前基于全面基因表达分析或RNAi文库的遗传学方法导致发现了与MEK抑制剂内在抗性相关的因素，但尚未开发出与MEK抑制剂可行的联合治疗方法。在这里，我们表明化学蛋白质信息学方法可以识别克服MEK抑制诱导的细胞死亡抗性的配体以及赋予这种抗性的靶分子。首先，我们使用天然产物紫苏醇和芝麻素醇，它们与MEK抑制剂曲美替尼联合诱导细胞死亡，作为化学探针，并确定核糖体蛋白S5（RPS5）为它们的共同靶蛋白。一致地，曲美替尼通过上调凋亡蛋白BIM和PUMA在RPS5缺失的癌细胞中诱导细胞死亡。然后，我们使用分子对接和分子动力学（MD）模拟，筛选FDA和EMA批准的用于RPS5结合配体的药物，发现乙酰水杨酸（ASA，也称为阿司匹林）直接与RPS5结合，导致BIM和PUMA上调并与曲美替尼联合诱导细胞死亡。我们的化学蛋白质信息学方法表明，RPS5赋予对MEK抑制剂诱导的细胞死亡的抗性，并且阿司匹林可以通过与RPS5结合而重新用于使细胞对MEK抑制敏感。
