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Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality [Microarray]

ABSTRACT: Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality [Microarray]

PROVIDER: PRJNA839235 | ENA |

REPOSITORIES: ENA

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Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality.

Project description:Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality.

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Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality [PooledCRISPR].

Project description:Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality [PooledCRISPR].

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Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality [Microarray]

Project description:Chromosomal instability (CIN) drives tumor heterogeneity, complicating cancer therapy. Although Polo-like kinase 1 (PLK1) overexpression induces CIN, direct inhibition of PLK1 has shown limited clinical benefits. We therefore performed a genome-wide synthetic dosage lethality (SDL) screen to identify effective alternative targets and validated over 100 candidates using in vivo and in vitro secondary CRISPR screens. We employed direct-capture Perturb-seq to assess the transcriptional consequences and viability of each SDL perturbation at a single-cell resolution. This revealed IGF2BP2 as a critical genetic dependency that, when targeted, downregulated PLK1 and significantly restricted tumor growth. Mechanistic analyses showed that IGF2BP2 loss disrupted cellular energy metabolism and mitochondrial ATP production by downregulating PLK1 levels as well as genes associated with oxidative phosphorylation. Consistent with this, pharmacological inhibition of IGF2BP2 severely impacts the viability of PLK1-overexpressing cancer cells addicted to higher metabolic rates. Our work offers a novel therapeutic strategy against PLK1-driven heterogeneous malignancies. We used microarray to identify synthetic dosage lethal partner genes PLK1

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Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality [PooledCRISPR].

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Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality.

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-05-09 | GSE203242 | GEO

Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models

Project description:We report the expression profiles of 21 T- and NK-cell lymphomas to provide a platform for further investigation of targetable vulnerabilities in diseases represented by these cell lines

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Identification of targetable epigenetic vulnerabilities for uveal melanoma

Project description:Identification of targetable epigenetic vulnerabilities for uveal melanoma

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PLK1 inhibition induces synthetic lethality in Fanconi anemia pathway-deficient acute myeloid leukemia

Project description:Overall survival of acute myeloid leukemia (AML) remains limited. Inhibitors of the master mitotic kinase PLK1 have emerged as promising therapeutics, demonstrating efficacy in an undefined subset of AML patients. However, the clinical success of PLK1 inhibitors remains hindered by a lack of predictive biomarkers. The Fanconi anemia (FA) pathway, a tumor-suppressive network comprised of at least 22 genes, is frequently mutated in sporadic AML. Here, we demonstrate that FA pathway disruption sensitizes AML cells to PLK1 inhibition. Mechanistically, we identify novel interactions between PLK1 and both FANCA and FANCD2 at mitotic centromeres. We demonstrate that PLK1 inhibition impairs recruitment of FANCD2 to mitotic centromeres, induces damage to mitotic chromosomes, and triggers mitotic collapse in FANCA-deficient cells. Our findings indicate that PLK1 inhibition targets mitotic vulnerabilities specific to FA pathway-deficient cells and implicate FA pathway mutations as potential biomarkers for the identification of patients likely to benefit from PLK1 inhibitors.

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Project description:Myelofibrosis (MF) is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. MF patients frequently carry driver mutations in JAK2 and Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across MF patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three therapeutic vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high MAPK-Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high ER stress, responding to ER stressors and UPR inhibition. Overall, our integrated analyses provide a molecularly-motivated roadmap for individualized MF patient treatment.

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