由于获得性耐药性，癌症治疗常常变得无效。为了表征乳腺癌细胞随着对致癌转录因子 FOXM1 抑制剂产生耐药性而发生的变化，我们研究了 FOXM1 抑制剂耐药细胞中细胞死亡途径的抑制，特别是铁死亡。我们还探讨了铁死亡激活剂是否可以与 FOXM1 抑制剂协同作用并克服 FOXM1 抑制剂耐药性。在用 FOXM1 抑制剂 NB73 和铁死亡激活剂二氢青蒿素和 JKE1674 单独或联合治疗的雌激素受体阳性和三阴性乳腺癌细胞中，我们测量了抑制作用FOXM1 抑制剂对乳腺癌细胞生长的抑制伴随着细胞死亡的增加以及线粒体形态和代谢活性的改变。低剂量的 FOXM1 抑制剂与铁死亡诱导剂强烈协同作用，降低细胞活力、迁移、集落形成和增殖相关基因的表达，并增加细胞内 Fe 2 和脂质过氧化（铁死亡标志物）。对 FOXM1 抑制的获得性抗性与癌症干细胞标记物和抑制铁死亡的蛋白质表达增加有关，从而使细胞存活并产生耐药性。值得注意的是，耐药细胞仍然对低剂量铁死亡激活剂的生长抑制敏感，从而有效地克服了获得性耐药性。描述可以克服耐药性的活力和细胞死亡途径的变化应该有助于确定可能最好地预防或逆转耐药性的方法。 FOXM1 的治疗靶向并最终改善患者的临床结果。© 2024。作者。

Cancer treatments often become ineffective because of acquired drug resistance. To characterize changes in breast cancer cells accompanying development of resistance to inhibitors of the oncogenic transcription factor, FOXM1, we investigated the suppression of cell death pathways, especially ferroptosis, in FOXM1 inhibitor-resistant cells. We also explored whether ferroptosis activators can synergize with FOXM1 inhibitors and can overcome FOXM1 inhibitor resistance.In estrogen receptor-positive and triple-negative breast cancer cells treated with FOXM1 inhibitor NB73 and ferroptosis activators dihydroartemisinin and JKE1674, alone and in combination, we measured suppression of cell viability, motility, and colony formation, and monitored changes in gene and protein pathway expressions and mitochondrial integrity.Growth suppression of breast cancer cells by FOXM1 inhibitors is accompanied by increased cell death and alterations in mitochondrial morphology and metabolic activity. Low doses of FOXM1 inhibitor strongly synergize with ferroptosis inducers to reduce cell viability, migration, colony formation, and expression of proliferation-related genes, and increase intracellular Fe+2 and lipid peroxidation, markers of ferroptosis. Acquired resistance to FOXM1 inhibition is associated with increased expression of cancer stem-cell markers and proteins that repress ferroptosis, enabling cell survival and drug resistance. Notably, resistant cells are still sensitive to growth suppression by low doses of ferroptosis activators, effectively overcoming the acquired resistance.Delineating changes in viability and cell death pathways that can overcome drug resistance should be helpful in determining approaches that might best prevent or reverse resistance to therapeutic targeting of FOXM1 and ultimately improve patient clinical outcomes.© 2024. The Author(s).