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Rebound after MAPK inhibitor withdrawal in pLGG cells

ABSTRACT: An in vitro MAPK inhibitor withdrawal rebound model was generated using the patient-derived, PXA-like cell line BT-40 (BRAFV600E, CDKN2Adel). Using this model, we investigated potential cellular intrinsic and extrinsic mechanisms involved in rebound growth in pLGG through multi-omics analysis (RNAseq, phospho-/proteomics).

ORGANISM(S): Homo sapiens

PROVIDER: GSE249718 | GEO | 2024/04/17

REPOSITORIES: GEO

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Rebound after MAPK inhibitor withdrawal in pLGG cells

Project description:An in vitro MAPK inhibitor withdrawal rebound model was generated using the patient-derived, PXA-like cell line BT-40 (BRAFV600E, CDKN2Adel). Using this model, we investigated potential cellular intrinsic and extrinsic mechanisms involved in rebound growth in pLGG through multi-omics analysis (RNAseq, phospho-/proteomics).

2024-04-17 | PXD048277 | Pride

Rebound after MAPK inhibitor withdrawal in pLGG cells

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Withdrawal of MEK1/2 inhibitor reverses acquired resistance driven by BRAF amplification but drives EMT and chemoresistance in cells with amplified KRAS

Project description:Acquired resistance to MEK1/2 inhibitors can arise through amplification of BRAFV600E or KRASG13D to reinstate ERK1/2 signalling. Here we show that BRAFV600E amplification and selumetinib resistance are fully reversible following drug withdrawal. Resistant cells with BRAFV600E amplification become addicted to selumetinib to maintain a precise level of ERK1/2 signalling (2-3% of total ERK1/2 active, here quantified by mass spectrometry), that is optimal for cell survival and proliferation. The magnitude of ERK1/2 activation following selumetinib withdrawal (~20% active) drives a p57KIP2-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, which selects against those cells with amplified BRAFV600E. ERK1/2-dependent p57KIP2 expression is required for loss of BRAFV600E amplification and determines the rate of reversal of selumetinib resistance. Furthermore, growth of selumetinib-resistant cells with BRAFV600E amplification as tumour xenografts is inhibited in mice that do not receive selumetinib. Thus, BRAFV600E amplification confers a selective disadvantage during drug withdrawal, providing a rationale for intermittent dosing to forestall resistance. In striking contrast, selumetinib resistance driven by KRASG13D amplification is not reversible. In these cells ERK1/2 reactivation does not inhibit proliferation but drives a ZEB1-dependent epithelial-to-mesenchymal transition that increases cell motility and promotes resistance to traditional chemotherapy agents arguing strongly against the use of ‘drug holidays’ in cases of KRASG13D amplification.

2019-03-11 | GSE120993 | GEO

HEK293T cell nuclear & cytosolic phospho-proteome remodelling upon amino acid withdrawal. Related to Supplementary Table 4 from An et al (2020)

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Exploiting drug addiction mechanisms to select against MAPKi resistant melanoma

Project description:Melanoma resistant to MAPK inhibitors (MAPKi) displays loss of fitness upon experimental MAPKi withdrawal and, clinically, may be resensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi addiction in MAPKi-resistant BRAF MUT or NRAS MUT melanoma. MAPKi-addiction phenotypes evident upon drug withdrawal spanned transient cell-cycle slowdown to cell-death responses, the latter of which required a robust phosphorylated ERK (pERK) rebound. Generally, drug withdrawal–induced pERK rebound upregulated p38–FRA1–JUNB–CDKN1A and downregulated proliferation, but only a robust pERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi addiction across the board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos related cell death. Specifically in MEKi-resistant NRAS MUT or atypical BRAF MUT melanoma, treatment with a type I RAF inhibitor intensified pERK rebound elicited by MEKi withdrawal, thereby promoting a cell death–predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi addiction.

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Chronic Pentylenetetrazol withdrawal induced successive gene expression changes in Drosophila head

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Pentylenetetrazol treatment and its withdrawal induced gene expression changes in female Drosophila head

Project description:We have recently developed a Drosophila behavioral- and transcriptomic- based (systems) model of chronic pentylenetetrazole (PTZ) induced locomotor plasticity. Pharmacological validation using antiepileptic drugs (AEDs) shows that the model is predictive of antiepileptic, antiepileptogenic, disease-modifying and neuroprotective activities. This model is however developed using male flies. The present submission relates to microarray gene expression profiling of fly heads after treatment of female Drosophila adults with PTZ for seven days subsequent withdrawal of PTZ for next seven days. Expression profiles have been generated at three time points during chronic PTZ treatment, namely 12 hrs, 2nd day and 7th day and at the end of withdrawal period, i.e., 14th day from the beginning of the treatment. Keywords: Drug response

2008-03-25 | GSE10852 | GEO

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Project description:Gene expression changes upon drug withdrawal

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Transcriptional characterization of cocaine withdrawal versus extinction within nucleus accumbens

Project description:Neurobiological alterations seen in addiction amplify during abstinence and compromise relapse prevention. Cocaine use disorder (CUD) exemplifies this phenomenon in which reward regions such as nucleus accumbens (NAc) undergo withdrawal-associated modifications. While genome-wide transcriptional changes in NAc are linked to specific addiction phases, these have not been examined in a context- and NAc-subregion-specific manner during withdrawal vs. extinction. We used cocaine self-administration in rats combined with RNA-sequencing of NAc core and shell to transcriptionally profile withdrawal in the home-cage, in the previous drug context, or after extinction. As expected, home-cage withdrawal maintained drug seeking, whereas extinction reduced it. Conversely, withdrawal involving the drug context increased seeking. Bioinformatic analyses revealed specific gene expression patterns and networks associated with these states. Comparing NAc datasets of CUD patients highlighted conserved transcriptomic signatures with rats experiencing withdrawal in the drug context. Together, this work reveals fundamental mechanisms that can be targeted to attenuate relapse.

2025-01-13 | GSE264129 | GEO

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