1. Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor.
- Author
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Moure CJ, Vara B, Cheng MM, Sondey C, Muise E, Park E, Vela Ramirez JE, Su D, D'Souza S, Yan Q, Yeung CS, Zhang M, Mansueto MS, Linn D, Buchanan M, Foti R, DiMauro E, Long B, Simov V, and Barry ER
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Xenograft Model Antitumor Assays, Small Molecule Libraries pharmacology, TEA Domain Transcription Factors, Cell Proliferation drug effects, Hepatocyte Growth Factor metabolism, Transcription Factors metabolism, Transcription Factors antagonists & inhibitors, Proto-Oncogene Proteins c-met antagonists & inhibitors, Proto-Oncogene Proteins c-met metabolism, Signal Transduction drug effects, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing antagonists & inhibitors, YAP-Signaling Proteins, Drug Resistance, Neoplasm drug effects
- Abstract
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 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. In addition, 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., (©2024 American Association for Cancer Research.)
- Published
- 2024
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