Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2–α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure.

致癌病变上调生物能量要求高的细胞过程，例如蛋白质合成，以驱动癌细胞生长和持续增殖。然而，致癌途径劫持这些关键过程会带来繁重的细胞应激，必须通过细胞生存的适应性反应来减轻这种应激。这些适应性反应的建立机制、它们对肿瘤发展的功能性影响以及它们对治疗干预的影响仍然很大程度上未知。使用前列腺癌 (PCa) 的小鼠和人源化模型，我们发现未折叠蛋白反应的三个分支之一在晚期 PCa 中被选择性激活。这种适应性反应激活真核起始因子 2-α (P-eIF2α) 的磷酸化，将整体蛋白质合成重置到促进侵袭性肿瘤发展的水平，并且是获得多个致癌病变后患者生存率较差的标志。使用患者来源的异种移植模型和 P-eIF2α 活性抑制剂 ISRIB，我们的数据表明，针对蛋白质合成的这种适应性制动可选择性地触发针对侵袭性转移性 PCa 的细胞毒性，而侵袭性转移性 PCa 是一种目前无法治愈的疾病。