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Tracing the lineage of replicative RNAs carrying MEK1 in the evolution of drug resistance

ABSTRACT: Drug resistance poses a significant clinical challenge, and comprehending the mechanisms underlying this resistance can facilitate the design of novel inhibitors and advance cancer treatment. The REPLACE system was employed to examine resistance mutations in MEK1 during the administration of 3 allosteric inhibitors. To explore the accumulation of mutations in various RNAs during the MEK1 evolution experiment, we established a barcoded library and conducted lineage tracing of replicative RNAs carrying MEK1 throughout the drug resistance evolution process.

ORGANISM(S): Mesocricetus auratus

PROVIDER: GSE271875 | GEO | 2024/09/30

REPOSITORIES: GEO

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Evolution of drug resistance enabled by replicative RNAs carrying MEK1

Project description:Drug resistance poses a significant clinical challenge, and comprehending the mechanisms underlying this resistance can facilitate the design of novel inhibitors and advance cancer treatment. The REPLACE system was employed to examine resistance mutations in MEK1 during the administration of 3 allosteric inhibitors (i.e., cobimetinib, trametinib, and selumetinib). These experiments represent a category of experiments that utilize REPLACE to achieve continuous evolution (or adaptation) by linking the activity of evolutionary targets with the survival of mammalian cells.

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Evolution of drug resistance enabled by replicative RNAs carrying MEK1

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Differential patterns of protein expression in monolayer or spheroid melanoma cell models of acquired resistance to BRAF and MEK1/2 inhibitors

Project description:Mitogen activated protein kinase (MAPK) inhibitors are important therapies for treating many cancers. However, the development of acquired resistance to most protein kinase inhibitors limit their ability to provide durable responses. Approximately 50% of malignant melanomas contain activating mutations in the BRAF kinase, which promote cancer cell survival by activating the extracellular signal-regulated kinase-1/2 (ERK1/2) pathway through direct phosphorylation of the MAPK/ERK kinase-1/2 (MEK1/2). Although combination treatment with BRAF and MEK1/2 inhibitors is a recommended approach to treat melanoma, the development of drug resistance remains a barrier to achieving long term patient benefits. Using high-resolution label-free mass spectrometry, the current studies compared relative protein changes in BRAF and MEK1/2 inhibitor resistant A375 melanoma cells grown as monolayers or 3D spheroids. While approximately 66% of proteins identified were common in both monolayer and spheroid cultures, only 6.2% or 3.6% of proteins that significantly increased or decreased, respectively, compared to drug sensitive cells were common between the drug-resistant monolayer and spheroid cells. Major changes in drug-resistant monolayers suggested upregulation of alternative kinase signaling pathways that promote growth and metastasis. In contrast, the major changes in drug-resistant spheroids indicated increased catabolic metabolism to support oxidative phosphorylation and energy requirements.

2022-02-17 | PXD026952 | Pride

Tracing the lineage of replicative RNAs carrying MEK1 in the evolution of drug resistance

Project description:Tracing the lineage of replicative RNAs carrying MEK1 in the evolution of drug resistance

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Analyzing the process of mutation accumulation in MEK1 evolution experiment using amplicon sequencing

Project description:Directed evolution in mammalian cells can facilitate the engineering of mammalian-compatible biomolecules and can enable synthetic evolvability for mammalian cells. We engineered an orthogonal alphaviral RNA replication system to evolve synthetic RNA-based devices, enabling RNA replicase-assisted continuous evolution (REPLACE) in live mammalian cells. we employed REPLACE to drive the continuous intracellular evolution of the cancer-related protein MEK1 with the aim of conferring resistance to Cobimetinib. To investigate the accumulation of mutations during this evolutionary process, we conducted amplicon sequencing on experimental materials collected at different stages. The results revealed intricate relationships among different mutations, highlighting the complex nature of the evolutionary landscape.

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Analysis of A375 and A375 clones that acquired resistance to GSK2118436 after treatment with GSK2118436 (GSK436), GSK1120212 (GSK212), or the combination of GSK2118436 and GSK1120212 for 24 hour

Project description:In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS – Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212. This data set was published in Molecular Cancer Therapeutics with the title “Combined inhibition of BRAF and MEK, BRAF and PI3K/mTOR, or MEK and PI3K/mTOR overcomes acquired resistance to the BRAF inhibitor GSK2118436, mediated by NRAS or MEK mutations” by Greger, J.G., et.al. A375 and 16R6-4 (an A375 derived GSK2118436 resistance clone) were treated for 24 hours with 0.1 micromolar GSK2118436, 1 micromolar GSK2118436, 0.01 micromolar GSK1120212, 0.1 micromolar GSK2118436 + 0.01 micromolar GSK1120212, or 1 micromolar GSK2118436 + 0.01 micromolar GSK1120212.

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Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer

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2024-06-16 | PXD043559 | Pride

Analysis of A375 and A375 clones that acquired resistance to GSK2118436 after treatment with GSK2118436 (GSK436), GSK1120212 (GSK212), or the combination of GSK2118436 and GSK1120212 for 24 hour

2012-02-01 | GSE35230 | GEO

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

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