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Activation of hepatocyte growth factor (HGF)/MET signaling as a mechanism of acquired resistance to a novel YAP1/TEAD small molecule inhibitor.

GSE249903 Homo sapiens (human) RNA-seq (gene expression) 49 samples Submitted 2024/03/26 Platform GPL24676
At a glance

RNA-seq (gene expression) · human · 49 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Homo sapiens (human)
Topic
MesotheliomaThis series is part of our curated briefing on it.
Samples
49 samples: 13 conditions, mostly in triplicateGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule InhibitorMolecular cancer therapeutics · 2024
Summary (written by the submitters)
Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity.
Read the full summary ↓
We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity. In vivo, MRK-A showed a favorable tolerability profile in mice and demonstrated pharmacokinetics suitable for twice daily (BID) oral dosing in preclinical efficacy studies. Importantly, monotherapeutic targeting of YAP1/TEAD in preclinical models generated regressions in a mesothelioma CDX model; however, rapid resistance to therapy was observed. RNA-sequencing of resistant tumors revealed mRNA expression changes correlated with the resistance state and a marked increase of hepatocyte growth factor (HGF) expression. In vitro, exogenous HGF was able to fully rescue cytostasis induced by MRK-A in mesothelioma cell lines. Additionally, co-administration of small molecule inhibitors of the MET receptor tyrosine kinase suppressed the resistance generating effect of HGF on MRK-A induced growth inhibition. In this work, we report the structure and characterization of MRK-A demonstrating potent and specific inhibition of YAP1/TAZ-TEAD mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling, including factors resulting in acquired drug resistance.
Published in
Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor
Moure CJ, Vara B, Cheng MM et al. · Molecular cancer therapeutics 2024 · PMID 38691847 · doi:10.1158/1535-7163.MCT-23-0538
This dataset
Open GSE249903 in finder → Find more human RNA-seq datasets → Mesothelioma landscape →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE249903_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1051111 and SRA study SRP477446. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 38691847) ↗
Study design
13 conditions, mostly in triplicate
NCI-H226, Xenograft, MRK-A, 30mpk 25d ×5 NCI-H226, Xenograft, MRK-A, 30mpk 46d ×5 NCI-H226, Xenograft, MRK-A, 30mpk 5d ×5 NCI-H226, Xenograft, Vehice 20d ×5 NCI-H226, Xenograft, Vehice 5d ×5 MSTO-211H, DMSO 48h ×3 MSTO-211H, DMSO 6h ×3 MSTO-211H, MRK-A 48h ×3 +5 more

Supports a between-group comparison across 49 samples.

How we read this: 13 replicated groups read from 49 sample titles; they account for 49 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

+ 9 more — browse all 49 samples with per-sample file links →

More Mesothelioma datasets

Search all human RNA-seq datasets in GEO →

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Metadata from NCBI GEO, cached and refreshed periodically — the NCBI page above is authoritative. Downloads link straight to NCBI/ENA; nothing is proxied through BioTransfer.