Treatment-persistent residual tumors impede curative cancer therapy. To understand this cancer cell state we generated models of treatment persistence that simulate the residual tumors. We observe that treatment-persistent tumor cells in organoids, xenografts, and cancer patients adopt a distinct and reversible transcriptional program resembling that of embryonic diapause, a dormant stage of suspended development triggered by stress and associated with suppressed Myc activity and overall biosynthesis. In cancer cells, depleting Myc or inhibiting Brd4, a Myc transcriptional co-activator, attenuates drug cytotoxicity through a dormant diapause-like adaptation with reduced apoptotic priming. Conversely, inducible Myc upregulation enhances acute chemotherapeutic activity. Maintaining residual cells in dormancy after chemotherapy by inhibiting Myc activity or interfering with the diapause-like adaptation by inhibiting cyclin-dependent kinase 9 represent potential therapeutic strategies against chemotherapy-persistent tumor cells. Our study demonstrates that cancer co-opts a mechanism similar to diapause with adaptive inactivation of Myc to persist during treatment.

持续治疗的残留肿瘤阻碍了治愈性癌症治疗。为了了解这种癌细胞状态，我们生成了模拟残留肿瘤的治疗持久性模型。我们观察到类器官、异种移植物和癌症患者中的治疗持续性肿瘤细胞采用独特且可逆的转录程序，类似于胚胎滞育，这是由压力触发的暂停发育的休眠阶段，与抑制的 Myc 活性和整体生物合成有关。在癌细胞中，消耗 Myc 或抑制 Brd4（一种 Myc 转录共激活因子）通过休眠的休眠样适应和减少的凋亡启动来减弱药物的细胞毒性。相反，诱导型 Myc 上调可增强急性化疗活性。通过抑制 Myc 活性或通过抑制细胞周期蛋白依赖性激酶 9 干扰滞育样适应来维持化疗后残留细胞处于休眠状态代表了针对化疗持久性肿瘤细胞的潜在治疗策略。我们的研究表明，癌症采用类似于滞育的机制，并在治疗期间持续存在 Myc 的适应性失活。