Abstract 42: Treatment-induced embryonic diapause-like adaptation through suppression of Myc activity as mediator of drug persistence in cancer

Abstract

Chemo-persistent residual tumors are a major barrier for curative cancer therapy and provide a reservoir of cancer cells for eventual relapse. This clinically critical tumor cell population is poorly understood and lacks faithful in vitro models. We compared the transcriptional profiles of paired samples from patient with solid tumors or hematological neoplasias at the stage of post-treatment residual tumors or minimal residual disease vs. at their respective baselines. For a large proportion of patients, post-treatment tumor cells had a molecular signature that resembled that of embryonic diapause, a dormant stage of suspended development in early mammalian embryos triggered by stress and induced by suppression of Myc activity and overall biosynthesis. This Myc-inactivated molecular program was acquired during treatment and not pre-existing at baseline. Remarkably, baseline tumors with multiple MYC copy numbers maintained their MYC amplification in the post-treatment persistent tumor cells but suppressed Myc activity. We simulated this cancer cell state using preclinical models of breast and prostate cancer and multiple myeloma, including patient-derived cancer organoids and PDX models. Parallel approaches of genome sequencing and DNA barcode-mediated clonal tracking in vitro and in vivo independently indicated that the residual cancer cell subpopulations that persisted after treatment with common chemotherapeutic classes were not driven by rare pre-existing clones or de novo genetic events. Transcriptional analysis of the treatment-persistent cancer cells in 3D organoid cultures and in xenograft/PDX models indicated a diapause-like transcriptional adaptation with inactivated Myc, similar to that in patients. We functionally examined the role of Myc suppression in in vitro models of breast cancer and multiple myeloma using genetic (CRISPR/Cas9 editing and interference) and pharmacological (inhibition of Myc transcriptional co-activator Brd4) approaches. Suppression of Myc in cancer cells induced an embryonic diapause-like molecular profile and attenuated the acute chemotherapeutic cytotoxicity. Myc-inactivated cancer cells had reduced apoptotic priming and maintained low redox stress even in the presence of cytotoxic agents, which may contribute to cell survival during treatment. High-throughput screening of chemo-persistent cells revealed that inhibitors of CDK9 could revert the biosynthetic pause, reactivate Myc, attenuate the diapause-like state, and re-sensitize the residual cancer cells to chemotherapy. Overall, our study shows that cancer cells can co-opt the stress survival mechanism of embryonic diapause by dynamically suppressing Myc to enter transient drug-refractory dormancy. Citation Format: Eugen Dhimolea, Ricardo De Matos Simoes, Dhvanir Kansara, Caroline Vilas, Aziz Al'Khafaji, Juliette Bouyssou, Aedin Culhane, Constantine S. Mitsiades. Treatment-induced embryonic diapause-like adaptation through suppression of Myc activity as mediator of drug persistence in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 42.

Drug-tolerant persister B-cell precursor acute lymphoblastic leukemia cells

“…Based on transcriptomics, different mechanisms have been proposed over time to explain tumor or leukemia cell persistence after drug treatment because of microenvironmental protection. Features identified in leukemia cells remaining after chemotherapy include dormancy and a diapause-like state (14,84,85). Based on numerous studies, it seems clear that indeed increased quiescence is a common feature of MRD cells in BCP-ALL as well: Turati et al ( 86), Ebinger et al (14) and our own studies all showed that MRD/DTP cells have reduced activity of MYC and E2F pathways.…”

Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse

“…Although many studies have been focused on the genetic mechanisms of drug resistance, emerging evidence suggests the importance of residual drug-tolerant persister (DTP) cancer cells, which survive the initial targeted therapy via diverse, reversible and non-mutational mechanisms, such as transcriptional, epigenetic, and metabolic reprogramming (16)(17)(18)(19)(20)(21)(22)(23). Recent studies have demonstrated an embryonic diapause-like adaption enabling the cancer treatment persistence (24,25). DTP cells, which underlie the phenomenon known as minimal residual disease (MRD), constitute a reservoir of slow-cycling cells that can drive irreversible acquired drug resistance upon long term drug treatment, which eventually leads to the cancer relapse (9)(10)(11)26).…”