An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

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. [Display omitted] •3D organoid cultures simulate the emergence of treatment-persistent residual tumors•Chemo-persister cells have suppressed Myc and a diapause-like molecular adaptation•Myc-suppressed cancer cells survive via reduced redox stress and apoptotic priming•CDK9 inhibition reverts biosynthetic pause and enhances chemosensitivity Dhimolea et al. document that cancer cell persistence during cytotoxic treatment is enabled by Myc inactivation and a biosynthetically paused adaptation resembling embryonic diapause. Myc-suppressed cancer cells have low redox stress and attenuated apoptotic priming. Interfering with this adaptive response of chemo-persistent cells enhances their chemosensitivity.