ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC [CRISPRi RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1271331 | ENA |
REPOSITORIES: ENA
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Project description:Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. However, upon treatment with K-Ras inhibitors, PDAC cancer cells undergo rapid metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. In this work, we demonstrate that this metabolic shift is associated with upregulation of the transcription factor ZBTB11, and both the metabolic state and the K-Ras inhibitor drug resistance can be attenuated by ZBTB11 depletion. We develop molecular glue degraders of ZBTB11 and demonstrate that they reprogram the aberrant transcriptome, proteome, metabolome, and bioenergetics of K-Ras inhibitor resistant PDAC, resensitizing them to K-Ras inhibition. ZBTB11 degradation leverages cell-type and cell-state specific differences in gene regulatory mechanisms controlling OXPHOS-pathway transcripts to selectively target the K-Ras inhibitor resistant state in PDAC while sparing hiPSC-derived neurons. Together, this work establishes ZBTB11 as a druggable vulnerability in K-Ras inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.
2025-07-15 | GSE298803 | GEO
Project description:Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. Upon treatment with K-Ras inhibitors, PDAC cancer cells undergo metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. However, direct inhibition of complex I is poorly tolerated in patients due to on-target induction of peripheral neuropathy. In this work, we develop molecular glue degraders against ZBTB11, a C2H2 zinc finger transcription factor that regulates the nuclear transcription of components of the mitoribosome and electron transport chain. Our ZBTB11 degraders leverage the differences in demand for biogenesis of mitochondrial components between human neurons and rapidly-dividing pancreatic cancer cells, to selectively target the K-Ras inhibitor resistant state in PDAC. Combination treatment of both K28 Ras inhibitor-resistant cell lines and multidrug resistant patient-derived organoids resulted in superior anti-cancer activity compared to single agent treatment, while sparing hiPSC-derived neurons. Proteomic and stable isotope tracing studies revealed mitoribosome depletion and impairment of the TCA cycle as key events that mediate this response. Together, this work validates ZBTB11 as a vulnerability in K-Ras inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.
2025-07-15 | PXD052360 | Pride
Project description:Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. However, upon treatment with K-Ras inhibitors, PDAC cancer cells undergo rapid metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. In this work, we demonstrate that this metabolic shift is associated with upregulation of the transcription factor ZBTB11, and both the metabolic state and the K-Ras inhibitor drug resistance can be attenuated by ZBTB11 depletion. We develop molecular glue degraders of ZBTB11 and demonstrate that they reprogram the aberrant transcriptome, proteome, metabolome, and bioenergetics of K-Ras inhibitor resistant PDAC, resensitizing them to K-Ras inhibition. ZBTB11 degradation leverages cell-type and cell-state specific differences in gene regulatory mechanisms controlling OXPHOS-pathway transcripts to selectively target the K-Ras inhibitor resistant state in PDAC while sparing hiPSC-derived neurons. Together, this work establishes ZBTB11 as a druggable vulnerability in K-Ras inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.
2025-07-15 | GSE298925 | GEO
Project description:ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC [Degrader RNA-seq]
| PRJNA1271833 | ENA
Project description:Hyperactive RAS/MAPK introduces cancer-specific mitotic vulnerabilities
| PRJNA723590 | ENA
Project description:Zbtb11 is an uncharacterised transcription factor that is conserved in vertebrates. Mutations in its human gene cause a form of inherited intellectual disablity, while in zebrafish Zbtb11 mutations lead to impaired hematopoesis and neruonal development. We used a combination of functional genomics approaches to determine its functions. To determine the genomic Zbtb11 binding locations, we carried out ChIP-seq using FLAG antibodies in a cell line with the endogenous Zbtb11 N-terminally tagged with FLAG (Zbtb11 FLAG/FLAG), as well as using an anti-Zbtb11 antibody in a wild type line. To determine the genes regulated by Zbtb11 we generated an inducible KO line (Zbtb11 lox/lox, Rosa26 ERt2-Cre) that allows the rapid depletion of Zbtb11 upon treatment with 4-hydroxytamoxyfen (4OHT). We treated Zbtb11 lox/lox, Rosa26 ERt2-Cre cells either with 4OHT (Zbtb11 KO) or ethanol (EtOH) as control, and subsequently performed directional RNA-seq from samples collected 48 hours post-treatment. As control for the effect of 4OHT on gene expression, we also compared Zbtb11 KO cells to wild type cells treated with 4OHT. The two ChIP-seq approaches showed very good overlap and allowed us to generate a set of high-confidence Zbtb11 binding sites common to both peak sets. We found Zbtb11 preferentially binds to a subset of house-keeping genes among which genes encoding proteins with mitochondrial functions are enriched. Upon Zbtb11 deletion, 154 genes changed expression 48 hours later, the vast majority of them down-regulated. Integration of ChIP-seq and RNA-seq data allowed us to identify the genes directly regulated by Zbtb11, and these were significantly enriched in genes with mitochondrial functions, with respiratory complex I and mitoribosome biogenesis being the overrepresented pathways. Subsequent biochemical experiments confirmed Zbtb11 is required for respiratory complex I assembly and for mitochondrial translation. In agreement with these findings Zbtb11 KO led to impaired respiration, proliferation arrest and cell death.
2020-01-14 | GSE125047 | GEO
Project description:Zbtb11 is a transcription factor conserved in vertebrates. Mutations in its human gene cause a form of inherited intellectual disablity, while in zebrafish Zbtb11 mutations lead to impaired hematopoesis and neruonal development. To determine the genes regulated by Zbtb11 we generated an inducible KO ES cell line (Zbtb11 lox/lox, Rosa26 ERt2-Cre) that allows the rapid depletion of Zbtb11 upon treatment with 4-hydroxytamoxyfen (4OHT). We subsequently performed RNA-seq in Zbtb11 KO and control cells to determine differentially expressed genes. Upon Zbtb11 deletion 310 genes changed expression. Integration of the RNA-seq data with Zbtb11 ChIP-seq data (GEO series GSE125047) allowed us to distinguish between genes directly regulated by Zbtb11 and indirect changes. 204 differentially expressed genes were bound by Zbtb11, while 106 did not have Zbtb11 binding sites. Directly regulated genes were significantly enriched in genes with mitochondrial functions, while indirectly controlled genes were enriched for p53 targets. In agreement with these findings Zbtb11 KO led to impaired respiration, proliferation arrest and cell death.
2022-12-31 | GSE130292 | GEO
Project description:ZBTB11 binding genes in NCI-H1299
2023-12-21 | GSE206958 | GEO
Project description:Pharmacological inhibition of oncogenic RAS represents an attractive strategy to target pancreatic ductal adenocarcinoma (PDAC), an almost ubiquitously RAS-driven disease. However, initial responses to targeted monotherapy inhibition of active RAS can be followed by relapses, potentially driven by the persistence of drug-tolerant tumor cells. To target these ‘persister’ cells, we investigated strategies to increase their immune visibility in mouse models of PDAC. We show that combining a RAS(ON) multi-selective inhibitor with the CDK4/6 inhibitor palbociclib drives persister cells into a senescent-like state, which coincides with improved tumor control and substantial remodeling of the tumor microenvironment. Combining RAS(ON) and CDK4/6 inhibition with a CD40 agonist results in durable regressions and CD4 T cell-dependent tumor-immune equilibrium. Our studies reveal a combinatorial approach that circumvents resistance to RAS(ON) inhibitor monotherapy in preclinical models and demonstrate a mechanism by which therapy-induced senescence can be reinforced by the immune system, resulting in durable tumor control.
2025-04-07 | GSE293456 | GEO
Project description:To determined ZBTB11 and SET regulates genes in NCI-H1299, we esteblished NCI-H1299 cell lines in which ZBTB11 and SET has been knocked down by si-RNA. We then conducted differential expressed genes analysis using data generated form RNA-seq of H1299 cell lines at the condition of two genes knocked down.
2023-12-21 | GSE206957 | GEO