Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells

ABSTRACT: Therapeutic resistance in cancer results from genetic or epigenetic mechanisms that enable cell survival under drug pressure. While several resistance mechanisms to cyclin-dependent kinase inhibitors have been identified, acquired resistance is still a therapeutic challenge. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDK4/6 inhibitor, or Telaglenestat, a glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenestat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growth in vivo, and Telaglenestat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenestat. The combination of Palbociclib and Telaglenestat may effectively forestall acquired resistance to Palbociclib.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245085 | GEO | 2025/07/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells

Project description:Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells

| PRJNA1026918 | ENA

Endogenous protein S100A14 stabilizes glutaminase to render hepatocellular carcinoma resistant to sorafenib

Project description:Many cases of advanced hepatocellular carcinoma (HCC) are resistant to the widely used drug sorafenib, which worsens prognosis. While many studies have explored how acquired resistance emerges during drug exposure, the mechanism underlying primary resistance before treatment still remain elusive. Here, we performed single-cell lineage tracing and RNA sequencing to identify sorafenib-resistant lineages in HCC, and demonstrated that high expression of S100A14 was positively associated with primary sorafenib resistance. Knocking down S100A14 rendered xenograft tumors in mice significantly more sensitive to sorafenib. Mechanistic studies indicated that S100A14 binds to glutaminase and blocks its phosphorylation at residues Y308 and S314, which in turn inhibits its ubiquitination and subsequent degradation. This stabilization of glutaminase reduces oxidative stress in HCC cells and thereby antagonizes the ability of sorafenib to induce apoptosis. Inhibiting glutaminase with telaglenastat (CB-839) significantly improved sorafenib efficacy against xenograft tumors in vivo. These results suggest that S100A14 can contribute to primary sorafenib resistance in HCC by stabilizing glutaminase. Thus, analyzing the expression of S100A14 may be useful for predicting primary sorafenib resistance, and inhibiting S100A14 or glutaminase may be effective for preventing or overcoming such resistance.

2025-03-02 | GSE282234 | GEO

Remodelling of H3K4me3 in response to long term drug treatment or oncogenic stress

Project description:Accumulating evidence indicates adaptive cellular reprogramming is a major contributor to disease recurrence and acquired drug resistance in cancer. Here we show that chronic drug exposure results in a multi-state metabolic and epigenetic adaption that allows cancer cells to regain proliferative capacity and eventually develop permanent drug resistance. Specifically, the escape from the previously described slow cycling induced drug tolerant cell state is driven by transiently increased expression of O-GlcNAc transferase (OGT) linking metabolic to epigenetic changes by facilitating global H3K4me3 remodeling. This adaptive process can be blocked by genetic or pharmacological inhibition of OGT or concurrent activation of AMPK to prevent metabolic adaption, subsequent epigenetic remodeling and permanent acquired drug resistance. This novel metabolic and epigenetic remodeling process is also observed following oncogene induced stress and the OGT dependence of this adaptive process uncovered promising targets for combination therapy with current standard of care drugs that could significantly increase response duration and patient outcomes.

2023-11-07 | GSE135605 | GEO

WM164 BRAF mutant Melanoma cells were treated with 500nM PLX4032 for 60 days and their gene expression was compared to parent cells exposed to a corresponding concentration of DMSO.

2022-01-01 | GSE136192 | GEO

RNA sequencing of luminal breast cancer patient-derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors

Project description:Combining CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has proven clinically effective and represents now the first-line treatment for advanced Luminal Breast Cancer (LBC) patients. However, resistance to CDK4/6i almost invariably arises in these patients, emphasising the critical need to comprehend these mechanisms and develop new strategies to overcome resistance. We report on the generation and characterisation of a LBC PDX displaying acquired resistance to CDK4/6i palbociclib. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumour shrinkage, some tumours might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that this PDX have become refractory to CDK4/6i, both at biological and molecular level.

2024-11-18 | E-MTAB-14085 | biostudies-arrayexpress

De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition

Project description:Cyclin-dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through integrated fluxomics and transcriptomics approaches, we show that the inhibition of CDK4/6 causes enhanced metabolism of glucose, glutamine and amino acids, a metabolic reprogramming directed by the MYC transcription factor. Upon inhibition of CDK4/6, MYC is stabilized and its accumulation induces an upregulation of the mTOR pathway and increased glutamine metabolism and production of α-ketoglutarate, a prolyl hydroxylase substrate that triggers HIF1α hydroxylation and degradation. These MYC-driven adaptations to CDK4/6 inhibition render cells highly sensitive to inhibitors of mTOR and glutaminase and to hypoxia, revealing that drug resistance can mechanistically promote the emergence of new vulnerabilities that can be exploited therapeutically. We used microarrays to detail the global programme of gene expression underlying inhibition of CDK4 and CDK6.

2017-09-15 | GSE84597 | GEO

Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer [scRNA-Seq]

Project description:BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs, and new vulnerabilities in cells after emergence of resistance.

2020-04-08 | GSE131984 | GEO

Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer [RNA-Seq]

2020-04-08 | GSE131983 | GEO

Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer [Exome]

2020-04-08 | GSE131980 | GEO

Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer [Barcode]

2020-04-08 | GSE131977 | GEO