Abstract：
Cancer cells lacking functional p53 exhibit poor prognosis, necessitating effective treatment strategies. Inhibiting WEE1, the G2/M cell cycle checkpoint gatekeeper, represents a promising approach for treating p53-deficient NSCLC. Here, we investigate the connection between p53 and WEE1, as well as explore a synergistic therapeutic approach for managing p53-deficient NSCLC. Our study reveals that p53 deficiency upregulates both protein levels and kinase activity of WEE1 by inhibiting its SUMOylation process, thereby enhancing the susceptibility of p53-deficient NSCLC to WEE1 inhibitors. Furthermore, we demonstrate that the WEE1 inhibitor Adavosertib induces intracellular lipid peroxidation, specifically in p53-deficient NSCLC cells, suggesting potential synergy with pro-oxidant reagents. Repurposing Disulfiram (DSF), an alcoholism medication used in combination with copper (Cu), exhibits pro-oxidant properties against NSCLC. The levels of WEE1 protein in p53-deficient NSCLC cells treated with DSF-Cu exhibit a time-dependent increase. Subsequent evaluation of the combination therapy involving Adavosertib and DSF-Cu reveals reduced cell viability along with smaller tumor volumes and lighter tumor weights observed in both p53-deficient cells and xenograft models while correlating with solute carrier family 7-member 11 (SLC7A11)/glutathione-regulated ferroptosis pathway activation. In conclusion, our findings elucidate the molecular interplay between p53 and WEE1 and unveil a novel synergistic therapeutic strategy for treating p53-deficient NSCLC.
摘要：
缺乏功能性p53的癌细胞预后不良，需要有效的治疗策略。抑制WEE1，G2/M细胞周期检查点看门人，代表了治疗p53缺陷型NSCLC的有希望的方法。这里,我们阐明p53和WEE1之间的联系,并探索治疗p53缺陷型NSCLC的协同治疗方法.我们的研究表明，p53缺乏通过抑制其SUMO化过程上调WEE1的蛋白质水平和激酶活性，从而增强p53缺陷型NSCLC对WEE1抑制剂的敏感性。此外，我们证明了WEE1抑制剂Adavosertib诱导细胞内脂质过氧化，特别是在缺乏p53的NSCLC细胞中，提示与促氧化剂药物的潜在协同作用。重修双硫仑（DSF），与铜（Cu）联合使用的酒精中毒治疗药物，表现出抗NSCLC的促氧化特性。DSF-Cu处理的p53缺陷型NSCLC细胞显示WEE1蛋白水平的时间依赖性增加。随后对涉及Adavosertib和DSF-Cu的联合疗法的评估显示，在p53缺陷细胞以及异种移植模型中观察到的细胞活力降低，肿瘤体积较小，肿瘤重量较轻，同时与溶质载体家族7成员11（SLC7A11）/谷胱甘肽调节的铁凋亡途径激活相关。总之,我们的研究结果阐明了p53和WEE1之间的分子相互作用,并揭示了治疗p53缺陷型NSCLC的新型协同治疗策略.
