死亡受体配体 TRAIL 是一种有前途的癌症治疗方法，因为它能够选择性触发癌细胞的外源性细胞凋亡。然而，基于 TRAIL 的人类疗法显示出局限性，主要是由于肿瘤细胞固有的或获得性的耐药性。为了解决这个问题，目前的工作重点是剖析参与 TRAIL 抗性的细胞内信号通路，以确定使癌细胞对 TRAIL 诱导的细胞毒性敏感的策略。在这项工作中，我们将致癌 MEK5-ERK5 通路描述为癌细胞抵抗死亡受体配体诱导的细胞凋亡的关键调节因子。使用 2D 和 3D 细胞培养物和转录组分析，我们表明 ERK5 控制 TP53INP2 的蛋白质稳态，TP53INP2 是响应 TNFα、FasL 或 TRAIL 完全激活 caspase-8 所必需的蛋白质。从机制上讲，ERK5 磷酸化并诱导 TP53INP2 泛素化和蛋白酶体降解，导致癌细胞对 TRAIL 产生耐药性。一致地，通过稳定TP53INP2，ERK5抑制或基因缺失使癌细胞对自然杀伤细胞表达的重组TRAIL和TRAIL/FasL诱导的细胞凋亡敏感。 MEK5-ERK5 通路调节癌细胞增殖和存活，ERK5 抑制剂已在实体瘤的临床前模型中显示出抗癌活性。使用子宫内膜癌患者来源的异种移植类器官，我们提出 ERK5 抑制作为一种有效策略，使癌细胞对基于 TRAIL 的疗法敏感。© 2023。作者。

Death receptor ligand TRAIL is a promising cancer therapy due to its ability to selectively trigger extrinsic apoptosis in cancer cells. However, TRAIL-based therapies in humans have shown limitations, mainly due inherent or acquired resistance of tumor cells. To address this issue, current efforts are focussed on dissecting the intracellular signaling pathways involved in resistance to TRAIL, to identify strategies that sensitize cancer cells to TRAIL-induced cytotoxicity. In this work, we describe the oncogenic MEK5-ERK5 pathway as a critical regulator of cancer cell resistance to the apoptosis induced by death receptor ligands. Using 2D and 3D cell cultures and transcriptomic analyses, we show that ERK5 controls the proteostasis of TP53INP2, a protein necessary for full activation of caspase-8 in response to TNFα, FasL or TRAIL. Mechanistically, ERK5 phosphorylates and induces ubiquitylation and proteasomal degradation of TP53INP2, resulting in cancer cell resistance to TRAIL. Concordantly, ERK5 inhibition or genetic deletion, by stabilizing TP53INP2, sensitizes cancer cells to the apoptosis induced by recombinant TRAIL and TRAIL/FasL expressed by Natural Killer cells. The MEK5-ERK5 pathway regulates cancer cell proliferation and survival, and ERK5 inhibitors have shown anticancer activity in preclinical models of solid tumors. Using endometrial cancer patient-derived xenograft organoids, we propose ERK5 inhibition as an effective strategy to sensitize cancer cells to TRAIL-based therapies.© 2023. The Author(s).