Many advanced therapeutics possess cytostatic properties that suppress cancer cell growth without directly inducing death. Treatment-induced cytostatic cancer cells can persist and constitute a reservoir from which recurrent growth and resistant clones can develop. Current management approaches primarily comprise maintenance and monitoring because strategies for targeting nonproliferating cancer cells have been elusive. Here, we used targeted therapy paradigms and engineered cytostatic states to explore therapeutic opportunities for depleting treatment-mediated cytostatic cancer cells. Sustained oncogenic AKT signaling was common, while nonessential, in treatment-mediated cytostatic cancer cells harboring PI3K-pathway mutations, which are associated with cancer recurrence. Engineering oncogenic signals in quiescent mammary organotypic models showed that sustained, aberrant activation of AKT sensitized cytostatic epithelial cells to proteasome inhibition. Mechanistically, sustained AKT signaling altered cytostatic state homeostasis and promoted an oxidative and proteotoxic environment, which imposed an increased proteasome dependency for maintaining cell viability. Under cytostatic conditions, inhibition of the proteasome selectively induced apoptosis in the population with aberrant AKT activation compared with normal cells. Therapeutically exploiting this AKT-driven proteasome vulnerability was effective in depleting treatment-mediated cytostatic cancer cells independent of breast cancer subtype, epithelial origin, and cytostatic agent. Moreover, transient targeting during cytostatic treatment conditions was sufficient to reduce recurrent tumor growth in spheroid and mouse models. This work identified an AKT-driven proteasome-vulnerability that enables depletion of persistent cytostatic cancer cells harboring PTEN–PI3K pathway mutations, revealing a viable strategy for targeting nonproliferating persistent cancer cell populations before drug resistance emerges. Significance: This study finds that sustained oncogenic signaling in therapy-induced cytostatic cancer cells confers targetable vulnerabilities to deplete persistent cancer cell populations and reduce cancer recurrence.

中文翻译：

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细胞静止状态下的持续致癌信号能够靶向非增殖性持续性癌细胞

许多先进的疗法具有细胞抑制特性，可以抑制癌细胞生长而不直接诱导死亡。治疗诱导的细胞抑制性癌细胞可以持续存在，并构成一个储存库，从中可以形成反复生长和耐药克隆。目前的管理方法主要包括维护和监测，因为针对非增殖癌细胞的策略一直难以捉摸。在这里，我们使用靶向治疗范例和工程细胞抑制状态来探索消除治疗介导的细胞抑制癌细胞的治疗机会。持续致癌 AKT 信号传导在治疗介导的含有 PI3K 通路突变的细胞抑制癌细胞中很常见，但不是必需的，而这些突变与癌症复发相关。在静止乳腺器官模型中工程致癌信号表明，AKT 的持续异常激活使细胞生长抑制上皮细胞对蛋白酶体抑制敏感。从机制上讲，持续的 AKT 信号传导改变了细胞静态稳态，促进了氧化和蛋白毒性环境，从而增加了维持细胞活力的蛋白酶体依赖性。在细胞抑制条件下，与正常细胞相比，抑制蛋白酶体可选择性诱导 AKT 激活异常的细胞凋亡。利用 AKT 驱动的蛋白酶体脆弱性进行治疗可有效消除治疗介导的细胞抑制癌细胞，而与乳腺癌亚型、上皮来源和细胞抑制剂无关。而且，在细胞抑制治疗条件下的瞬时靶向足以减少球体和小鼠模型中的复发性肿瘤生长。这项工作发现了 AKT 驱动的蛋白酶体脆弱性，能够消除含有 PTEN-PI3K 通路突变的持续性细胞抑制癌细胞，揭示了在出现耐药性之前针对非增殖性持续性癌细胞群的可行策略。意义：这项研究发现，治疗诱导的细胞抑制性癌细胞中持续的致癌信号传导具有可靶向的脆弱性，可以消除持久性癌细胞群并减少癌症复发。这项工作发现了 AKT 驱动的蛋白酶体脆弱性，能够消除含有 PTEN-PI3K 通路突变的持续性细胞抑制癌细胞，揭示了在出现耐药性之前针对非增殖性持续性癌细胞群的可行策略。意义：这项研究发现，治疗诱导的细胞抑制性癌细胞中持续的致癌信号传导具有可靶向的脆弱性，可以消除持久性癌细胞群并减少癌症复发。这项工作发现了 AKT 驱动的蛋白酶体脆弱性，能够消除含有 PTEN-PI3K 通路突变的持续性细胞抑制癌细胞，揭示了在出现耐药性之前针对非增殖性持续性癌细胞群的可行策略。意义：这项研究发现，治疗诱导的细胞抑制性癌细胞中持续的致癌信号传导具有可靶向的脆弱性，可以消除持久性癌细胞群并减少癌症复发。