scholarly journals The Influence of BCL6 on the WNT Pathway in Glioblastoma Therapy Resistance

2021 ◽  
Author(s):  
◽  
Rosemary Gordon-Schneider
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Wnt Pathway ◽  
Therapy Resistance ◽  
Level Of Activity ◽  
Apoptotic Protein ◽  
Molecule Inhibitor ◽  
Chemotherapeutic Treatment ◽  
Canonical Wnt ◽  
Cancerous Cells

<p>Glioblastoma is a devastating disease with a median survival of 18 months from diagnosis and a 5 years survival rate of only 10%. The gold standard of treatment for glioblastoma is surgical resection followed by chemotherapeutic treatment with Temozolomide, a DNA alkylating agent, and irradiation around the remaining tumour margins. These treatments are both designed to create DNA damage to the cancerous cells, causing the cell cycle to halt, and result in apoptosis. This treatment does extend patients life for a few months, however glioblastoma cells quickly become resistant to therapy, and disease is always fatal. The anti-apoptotic protein BCL6, confers resistance to apoptosis in response to DNA damage and has been shown to be upregulated in Glioblastoma in response to DNA damaging chemotherapy and irradiation. This upregulation has been hypothesised to increase resistance to these therapies. By minimizing resistance to the standard therapies, the outlook for sufferers of glioblastoma could be greatly improved. Dysregulation of the WNT pathway has also been shown to be very important in carcinogenesis of glioblastoma and is responsible for the diffuse nature of the tumour which makes total resection nearly impossible. An RNA-seq screen was carried out on a glioblastoma cell line in which BCL6 was inhibited using the small molecule inhibitor FX1. This resulted in a change in expression of a large number of WNT related genes. This indicates that there is a link between BCL6 and the WNT pathway. Changes in expression in the WNT genes DKK1, WNT5a and WNT5b were validated. Experiments were carried out to investigate the effects of chemotherapy and BCL6 inhibition on both the canonical and non-canonical WNT pathways. It was found that BCL6 has an influence of the level of activity of the canonical WNT pathway. It also influences migration, the cell cycle, and clonogenicity. Understanding this link between WNT and BCL6 could be crucial in finding an effective treatment for glioblastoma.</p>

scholarly journals The Influence of BCL6 on the WNT Pathway in Glioblastoma Therapy Resistance

2021 ◽  
Author(s):  
◽  
Rosemary Gordon-Schneider
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Wnt Pathway ◽  
Therapy Resistance ◽  
Level Of Activity ◽  
Apoptotic Protein ◽  
Molecule Inhibitor ◽  
Chemotherapeutic Treatment ◽  
Canonical Wnt ◽  
Cancerous Cells

<p>Glioblastoma is a devastating disease with a median survival of 18 months from diagnosis and a 5 years survival rate of only 10%. The gold standard of treatment for glioblastoma is surgical resection followed by chemotherapeutic treatment with Temozolomide, a DNA alkylating agent, and irradiation around the remaining tumour margins. These treatments are both designed to create DNA damage to the cancerous cells, causing the cell cycle to halt, and result in apoptosis. This treatment does extend patients life for a few months, however glioblastoma cells quickly become resistant to therapy, and disease is always fatal. The anti-apoptotic protein BCL6, confers resistance to apoptosis in response to DNA damage and has been shown to be upregulated in Glioblastoma in response to DNA damaging chemotherapy and irradiation. This upregulation has been hypothesised to increase resistance to these therapies. By minimizing resistance to the standard therapies, the outlook for sufferers of glioblastoma could be greatly improved. Dysregulation of the WNT pathway has also been shown to be very important in carcinogenesis of glioblastoma and is responsible for the diffuse nature of the tumour which makes total resection nearly impossible. An RNA-seq screen was carried out on a glioblastoma cell line in which BCL6 was inhibited using the small molecule inhibitor FX1. This resulted in a change in expression of a large number of WNT related genes. This indicates that there is a link between BCL6 and the WNT pathway. Changes in expression in the WNT genes DKK1, WNT5a and WNT5b were validated. Experiments were carried out to investigate the effects of chemotherapy and BCL6 inhibition on both the canonical and non-canonical WNT pathways. It was found that BCL6 has an influence of the level of activity of the canonical WNT pathway. It also influences migration, the cell cycle, and clonogenicity. Understanding this link between WNT and BCL6 could be crucial in finding an effective treatment for glioblastoma.</p>

scholarly journals Genomic hallmarks of cellular dormancy in cancer and therapeutic implications

2021 ◽  
Author(s):  
Maria Secrier ◽  
Anna Wiecek ◽  
Stephen Cutty ◽  
Daniel Kornai ◽  
Mario Parreno-Centeno ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Therapy Resistance ◽  
Therapeutic Resistance ◽  
Epigenetic Mechanisms ◽  
Therapeutic Implications ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Cell Data ◽  
Cell Cycle Kinase

Abstract Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative, quiescent or ‘dormant’ state, which is difficult to capture and whose mutational drivers remain largely unknown. We developed methodology to uniquely identify this state from transcriptomic signals and characterised its prevalence and genomic constraints in solid primary tumours. We show dormancy preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We uncover novel genomic dependencies of this process, including the amplification of the centrosomal gene CEP89 as a driver of dormancy impairment. Lastly, we demonstrate that dormancy underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single cell data, and propose a signature of dormancy-linked therapeutic resistance to further study and clinically track this state.

scholarly journals LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis

2019 ◽  
Author(s):  
Fang Zhang ◽  
Pengyi Yan ◽  
Huijing Yu ◽  
Huangying Le ◽  
Zixuan li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Rna Binding ◽  
Tumor Therapy ◽  
Genotoxic Stress ◽  
Therapy Resistance ◽  
List Type ◽  
M Cell

SummaryAttenuated DNA repair leads to genomic instability and tumorigenesis. BRCA1/BARD1 are the best known tumor suppressors that promote homology recombination (HR) and arrest cell cycle at G2/M checkpoint. As E3 ubiquitin ligases, their ubiquitinase activity has been known to involve in the HR and tumor suppression, but the mechanism remains ambiguous. Here, we demonstrated upon genotoxic stress, BRCA1 together with BARD1 catalyzed the K48 ployubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degraded it through 26S ubiquitin-proteasome pathway. Depleting LARP7 suppressed the expression of CDK1 complex, arrested cell at G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation which thereby facilitated RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast patients lead to the chemoradiotherapy resistance both in vitro and in vivo. Together, this study unveils a mechanism by which BRCA1/BARD1 utilizes their E3 ligase activity to control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy.HighlightsDNA damage response downregulates LARP7 through BRCA1/BARD1BRCA1/BARD1 catalyzes the K48 polyubiquitination on LARP7LARP7 promotes G2/M cell cycle transition and tumorigenesis via CDK1 complexLARP7 disputes homology-directed repair that leads to tumor therapy resistance

MLN4924, A Novel First in Class Small Molecule Inhibitor of the Nedd8 Activating Enzyme (NAE), Has Potent Activity in Preclinical Models of Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1021-1021
Author(s):  
Ronan T. Swords ◽  
Kevin R. Kelly ◽  
Peter G. Smith ◽  
James J. Gansey ◽  
Devalingam Mahalingam ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Small Molecule ◽  
Myeloid Leukemia ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Molecule Inhibitor ◽  
Acute Myeloid

Abstract Abstract 1021 Poster Board I-43 The coordinated balance between the synthesis and degradation of proteins is an important regulator of cancer cell biology. The ubiquitin-proteasome system (UPS) is responsible for the timed destruction of many proteins including key mediators of fundamental signaling cascades and critical regulators of cell cycle progression and transcription. Within the UPS, the E3 ligases are multi-protein complexes whose specificity is established by their individual components as well as post-translational modifications by various factors including the ubiquitin-like molecule, Nedd8. The Nedd8 activating enzyme (NAE) has been identified as an essential regulator of the Nedd8 conjugation pathway, which controls the activity of the cullin-dependent E3 ubiquitin ligases. The cullins direct the ubiquitination and subsequent degradation of many proteins with important roles in cell cycle progression (p27, cyclin E), DNA damage (Cdt-1), stress response (NRF-2, HIF1α) and signal transduction (IκBα). Acute myeloid leukemia (AML) is a disease of the elderly and prognosis is extremely poor with a median overall survival of just 2 months for untreated patients. As such, novel therapeutic strategies are urgently needed to improve clinical outcomes. Considering that Nedd8-mediated control of protein homeostasis is vitally important for the survival of AML cells, we hypothesized that disrupting this process would inhibit proliferation and induce cell death. We tested this hypothesis by investigating the preclinical anti-leukemic activity of MLN4924, a novel first in class small molecule inhibitor of the Nedd8 activating enzyme. MLN4924 induced DNA damage followed by rapid and selective caspase-dependent cell death in AML cell lines and primary AML cells from patients, but not in peripheral blood mononuclear cells from healthy donors. Transient exposure to MLN4924 impaired colony formation in a dose-dependent manner. Kinetic analysis of drug-induced effects on cell cycle distribution revealed that AML cells treated with MLN4924 initially arrested at the G1 transition prior to their subsequent accumulation in the sub-G1 compartment. Assays conducted using MV-411 cells with and without stable shRNA-mediated knockdown of FLT3 expression demonstrated that MLN4924 is highly effective independent of FLT3 status. Further investigation revealed that the activity of MLN4924 was preserved when cells were co-cultured with bone marrow stromal cells indicating that it has the ability to overcome the effects of stromal-mediated survival signaling that has been established to blunt the efficacy of relevant standard of care agents. MLN4924 induced a dose and time dependant increase in the expression of phospo-IκB, an important target for degradation through the Nedd8 conjugation pathway. The inhibitory effects of MLN4924 on NFκB were confirmed by demonstrating that the transcriptional activity of the NFκB p65 subunit was significantly reduced following drug exposure. Moreover, treatment of immunodeficient mice implanted with HL-60 human leukemia cells with MLN4924 led to an inhibition of neddylated cullins, accumulation of phospho-IκBα and achieved complete and stable disease regression. Our results indicate that MLN4924 is a highly promising novel agent for the treatment of AML and warrants further evaluation in clinical trials. Disclosures: Smith: Millennium Pharmaceuticals: Employment. Gansey:Millennium Pharmaceuticals: Employment.

scholarly journals The Roles of Cancer Stem Cells and Therapy Resistance in Colorectal Carcinoma

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1392 ◽  
Author(s):  
Plabon Kumar Das ◽  
Farhadul Islam ◽  
Alfred K. Lam
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Cancer Stem Cells ◽  
Colorectal Carcinoma ◽  
Deep Understanding ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Cell Cycle Checkpoints ◽  
Repair Capacity

Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies target proliferating and mature cancer cells, while CSCs are mostly quiescent and poorly differentiated, thereby they can easily survive chemotherapeutic insults. The aberrant activation of Wnt/β-catenin, Notch, Hedgehog, Hippo/YAP (Yes-associated protein) and phosphatidylinositol 3-kinase/protein kinase B facilitates CSCs with excessive self-renewal and therapy resistance property in CRC. CSCs survive the chemo-radiotherapies by escaping therapy mediated DNA damage via altering the cell cycle checkpoints, increasing DNA damage repair capacity and by an efficient scavenging of reactive oxygen species. Furthermore, dysregulations of miRNAs e.g., miR-21, miR-93, miR-203, miR-215, miR-497 etc., modulate the therapeutic sensitivity of colorectal CSCs by regulating growth and survival signalling. In addition, a reversible quiescent G0 state and the re-entering cell cycle capacity of colorectal CSCs can accelerate tumour regeneration after treatment. Moreover, switching to favourable metabolic signatures during a therapeutic regimen will add more complexity in therapeutic outcomes against CSCs. Therapeutic strategies targeting these underlying mechanisms of CSCs’ therapy resistance could provide a promising outcome, however, deep understanding and concerted research are necessary to design novel therapies targeting CSCs. To conclude, the understanding of these mechanisms of CSC in CRC could lead to the improved management of patients with CRC.

scholarly journals A Syx-RhoA-Dia1 signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in glioblastoma

2021 ◽  
Author(s):  
Wan-Hsin Lin ◽  
Ryan W. Feathers ◽  
Lisa M. Cooper ◽  
Laura J. Lewis-Tuffin ◽  
Jann N. Sarkaria ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Radiation Treatment ◽  
Therapy Resistance ◽  
Cell Cycle Regulators ◽  
Nucleotide Exchange ◽  
M Cell ◽  
Cycle Progression ◽  
Signaling Axis

AbstractGlioblastomas (GBM) are aggressive tumors that lack effective treatments. Here, we show that the Rho family guanine nucleotide exchange factor Syx promotes GBM cell growth both in vitro and in orthotopic GBM patient-derived xenografts. Growth defects upon Syx depletion are attributed to prolonged mitosis, increased DNA damage, G2/M cell cycle arrest, and cell apoptosis, mediated by altered mRNA and protein expression of various cell cycle regulators. These effects are phenocopied by depletion of the Rho downstream effector Dia1 and are due at least in part to increased cytoplasmic retention and reduced activity of the YAP/TAZ transcriptional coactivators. Further, targeting Syx signaling cooperates with radiation treatment and temozolomide (TMZ) to decrease viability in GBM cells irrespective of their inherent response to TMZ. Taken together, the data indicate that a Syx-RhoA-Dia1-YAP/TAZ signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in GBM and argue for its targeting for cancer treatment.One Sentence SummarySyx promotes growth and therapy resistance in glioblastoma.

MLN4924, a Potent and Novel Small Molecule Inhibitor of Nedd8 Activating Enzyme, Induces DNA Re-Replication and Apoptosis in Cultured Human Tumor Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3621-3621
Author(s):  
Michael Milhollen ◽  
Usha Narayanan ◽  
Jennifer Duffy ◽  
Ben Amidon ◽  
Teresa A Soucy ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Human Tumor ◽  
Human Tumor Cells ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Molecule Inhibitor ◽  
Hct 116 ◽  
Hct 116 Cells

Abstract Successful therapeutic intervention in the ubiquitin-proteasome system (UPS) in multiple myeloma and mantle cell lymphoma with proteasome inhibitors has led to the pursuit of additional targets within the UPS. Through this effort we have identified MLN4924, a novel, first-in-class small molecule inhibitor of Nedd8 activating enzyme (NAE) currently in Phase I trials in hematological and non-hematological malignancies. The initial step in the pathway for conjugation of the ubiquitin-like protein Nedd8 to its cellular targets requires the activity of NAE. Nedd8 conjugation is required for the proper function of mammalian cullin-dependent ubiquitin ligases (CDLs). These CDLs in turn control the timely ubiquitination and subsequent degradation of many proteins with important roles in cell cycle progression and signal transduction. Inhibition of NAE leads to decreased activity of the CDLs impacting cellular processes relevant to tumor cell growth and survival thereby providing a rationale for targeting NAE as an anti-cancer strategy. MLN4924 was used to explore the consequences of inhibiting the Nedd8 pathway in cultured human cancer cells. Here we show that MLN4924 has broad in vitro potency against several myeloma, lymphoma and leukemia cell lines including; RPMI-8226, NCI-H929, WSU-DLCL2, Ly10, Ly19, HL-60 and MOLT-4 respectively, as well as multiple non-hematological cell lines. MLN4924 specifically inhibits Nedd8-cullin formation leading to increased steady state levels of direct CDL substrates by preventing their ubiquitination and degradation through the proteasome. Many of these CDL substrates are involved in cell cycle progression. One such CDL substrate is the critical DNA replication licensing factor Cdt1. Over-expression of Cdt1 has been shown to induce DNA re-replication in cells resulting in DNA damage, cell cycle arrest and genomic instability. Here we show that MLN4924 dramatically affects the cell cycle distribution of HCT-116 and WSU-DLCL2 cells resulting in S-phase accumulation and apparent increase in nuclear size and DNA content. HCT-116 cells treated with MLN4924 showed an increased and prolonged ability to incorporate BrdU demonstrating active DNA synthesis in S-phase consistent with over replication of the DNA. Aphidicolin synchronized HCT-116 cells released into MLN4924 did not progress into mitosis as exhibited by the absence of the mitotic marker pH3 (S10) suggesting that the observed phenotype was occurring within the same cell cycle. Immunoflourescence and western blot analysis of HCT-116 cells treated with MLN4924 also showed an increase in the nuclear localization and stabilization of Cdt1 consistent with the hypothesis that MLN4924 disrupts the normal cell cycle regulation and turnover of this CDL substrate. The aberrant re-replication phenotype observed following MLN4924 treatment in HCT-116 and WSU-DLCL2 cells was associated with the activation of a DNA damage checkpoint response through the ATM/ATR pathways assessed by the expression of elevated levels of phospho-p53(S15), phospho-Chk1(S317) and phospho-H2AX(S139). Western blot analysis of aphidicolin synchronized HCT-116 cells released into MLN4924 demonstrated the sequential nature of the DNA damage response consistent with the re-replication phenotype. The initial appearance of ssDNA breaks (phosph-Chk1 and phospho-Rad17) presumably resulting from stalled replication forks, illustrated early ATR activation followed by the induction of the ATM pathway as a result of dsDNA breaks ( phospho-Chk2 and phospho-NBS1). Finally the cells inability to recover from the dsDNA damage resulted in apoptosis as demonstrated by the appearance of cleaved caspase-3 and cleaved PARP. The gross accumulation of over replicated DNA and DNA-damage following NAE inhibition resulting in cell cycle arrest and apoptosis is consistent with DNA re-replication and demonstrates a novel mechanism of action for MLN4924 in cultured human tumor cells. These data have important implications for the use of MLN4924 in hematological malignancies as a single agent, and potentially in combination with other therapies.

Inhibition of CHK1 Enhances Cell Death Induced By the Bcl-2-Selective Inhibitor ABT-199 in Acute Myeloid Leukemia Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2469-2469
Author(s):  
Jianyun Zhao ◽  
Xiaojia Niu ◽  
Holly Edwards ◽  
Yue Wang ◽  
Jeffrey W Taub ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Selective Inhibitor ◽  
Intrinsic Resistance ◽  
Apoptotic Protein ◽  
Wide Range ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) remains a challenging disease to treat in both pediatric and adult populations. Resistance to cytarabine (ara-C) and anthracycline [e.g., daunorubicin (DNR)]-based chemotherapy is a major cause of treatment failure in this disease. Therefore, more effective therapies are urgently needed to improve treatment outcome of AML patients. Anti-apoptotic Bcl-2 family proteins play key roles in the apoptosis pathway. Overexpression of these proteins is associated with chemoresistance and poor clinical outcome. Thus, much attention has been focused on inhibition of the anti-apoptotic Bcl-2 family proteins for the treatment of various malignancies. ABT-199 is a selective Bcl-2 inhibitor that has demonstrated promising results in CLL, as well as other malignancies including AML. We previously demonstrated that ABT-199 has a wide range of activity in AML cells. In addition, we have also identified that the anti-apoptotic protein Mcl-1, in conjunction with the pro-apoptotic protein Bim, is a key player in resistance to ABT-199 in AML cells. Thus, combining ABT-199 with agents that downregulate Mcl-1 could overcome the intrinsic resistance to ABT-199. Checkpoint kinase 1 (CHK1) is a protein kinase which plays a central role in the DNA damage response (DDR). The DDR represents a complex network of multiple signaling pathways involving cell cycle checkpoints, DNA repair, transcriptional programs, and apoptosis, through which cells maintain genomic integrity following various endogenous or environmental stresses. Inhibition of CHK1 has been demonstrated to induce DNA damage. We and others have also demonstrated that DNA damage results in downregulation of Mcl-1. Thus, it is conceivable that targeting CHK1 may enhance the cytotoxic effects of ABT-199 on AML cells through downregulation of Mcl-1. In this study, we investigated the combination of LY2603618, a CHK1-selective inhibitor, and the Bcl-2 inhibitor ABT-199 in AML cell lines and primary patient samples. We demonstrated that LY2603618 inhibited proliferation of AML cell lines (n=11) and diagnostic blasts (n=26). Interestingly, all 11 AML cell lines and 23 out of the 26 primary AML patient samples tested showed a LY2603618 IC50 lower than the Cmax of LY2603618 (~9 µM) determined in Phase I clinical studies. Annexin V and propidium iodide (PI) staining and flow cytometry analyses revealed that LY2603618 induced Bak-dependent apoptosis in AML cells. As expected, treatment of AML cells with LY2603618 resulted in abolishment of G2 cell cycle check point and DNA double strand breaks (DSBs), which could be, at least partially, blocked by a CDK inhibitor, roscovitine. LY2603618 treatment also resulted in downregulation of Mcl-1, which coincided with the initiation of apoptosis. Overexpression of Mcl-1 in AML cells significantly attenuated apoptosis induced by LY2603618, confirming the critical role of Mcl-1 in apoptosis induced by the agent. Consistent with our hypothesis, simultaneous combination of LY2603618 and ABT-199 resulted in synergistic induction of apoptosis in both AML cell lines and primary patient samples. Our results demonstrate that LY2603618 synergizes with ABT-199 in AML cells. Our findings provide new insights into overcoming the mechanism of ABT-199 resistance in AML cells and support the clinical development of the combination of ABT-199 and CHK1 inhibitors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Genomic hallmarks of cellular dormancy in cancer and therapeutic implications

2021 ◽  
Author(s):  
Anna J Wiecek ◽  
Stephen J Cutty ◽  
Daniel Kornai ◽  
Mario Parreno-Centeno ◽  
Lucie E Gourmet ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Therapy Resistance ◽  
Therapeutic Resistance ◽  
Epigenetic Mechanisms ◽  
Therapeutic Implications ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Cell Data ◽  
Cell Cycle Kinase

Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative, quiescent or "dormant" state, which is difficult to capture and whose mutational drivers remain largely unknown. We developed methodology to uniquely identify this state from transcriptomic signals and characterised its prevalence and genomic constraints in solid primary tumours. We show dormancy preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We uncover novel genomic dependencies of this process, including the amplification of the centrosomal gene CEP89 as a driver of dormancy impairment. Lastly, we demonstrate that dormancy underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single cell data, and propose a signature of dormancy-linked therapeutic resistance to further study and clinically track this state.

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