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ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC [CRISPRi RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298803 | GEO | 2025/07/15

REPOSITORIES: GEO

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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.

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ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC [CRISPRi RNA-seq]

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