NCBI Logo
GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
          Go
Series GSE249903 Query DataSets for GSE249903
Status Public on Mar 26, 2024
Title Activation of hepatocyte growth factor (HGF)/MET signaling as a mechanism of acquired resistance to a novel YAP1/TEAD small molecule inhibitor.
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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. 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.
 
Overall design RNA from two cell lines grown in vitro and treated with either vehicle or MRK-A for either 6 hr or 48 hr were sequenced. In addition, RNA from tumors grown in vivo in NSG mice following treatment with either Vehicle or MRK-A for either 5 days, or until the tumors reached 500 mm3. For the 500mm3 samples, MRK-A was dosed either for only 5 days, or continuously until 500mm3.
 
Contributor(s) Moure C, Muise E, Barry E
Citation(s) 38691847
Submission date Dec 11, 2023
Last update date Jun 25, 2024
Contact name Eric Muise
E-mail(s) eric_muise@merck.com
Phone 6179923514
Organization name Merck
Department GPGX
Street address 33 Ave. Louis Pasteur
City Boston
State/province MA
ZIP/Postal code 02115
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (49)
GSM7966727 MSTO-211H, DMSO 48h-1
GSM7966728 MSTO-211H, DMSO 48h-2
GSM7966729 MSTO-211H, DMSO 48h-3
Relations
BioProject PRJNA1051111

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE249903_counts.txt.gz 2.5 Mb (ftp)(http) TXT
GSE249903_fpkm.txt.gz 3.7 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record
| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap