Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma

Our plain-English summary of Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma, by L. Evsen, P.J. Morris, C.J. Thomas, et al (Pharmaceuticals, 2023).

The study

• Authors: L. Evsen, P.J. Morris, C.J. Thomas, M. Ceribelli
• Journal: Pharmaceuticals
• Published: 2023;16(12)
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The hippo signaling pathway is a central tumor suppressor cascade frequently inactivated in selected human cancers, leading to the aberrant activation of TEAD transcription factors. Whereas several TEAD auto-palmitoylation inhibitors are currently in development, a comprehensive assessment of this novel drug-modality is missing. Here, we report a comparative analysis among six TEADi(s) using cell-based and biochemical assays in Hippo pathway deficient mesothelioma. Our analysis revealed varying potency and selectivity across TEADi, also highlighting their limited efficacy. To overcome this limitation, we performed an unbiased, quantitative high-throughput drug screening by combining the TEADi VT-103 with a library of approximately 3000 oncology-focused drugs. By exploiting this library's mechanistic redundancy, we identified several drug-classes robustly synergized with TEADi. These included glucocorticoid-receptor (GR) agonists, Mek1/2 inhibitors, mTOR inhibitors, and PI3K inhibitors, among others. Altogether, we report a coherent single-agent dataset informing on potency and selectivity of TEAD-palmitoylation inhibitors as single-agents. We also describe a rational pipeline enabling the systematic identification of TEAD druggable co-dependencies. This data should support the pre-clinical development of drug combination strategies for the treatment of Hippo-deficient mesothelioma, and more broadly, for other cancers dependent on the oncogenic activity of YAP/TEAD.

In plain English

This was a laboratory study of drugs tested on cancer cells grown in dishes. It did not study people or asbestos exposure, and the article does not discuss asbestos. The authors compared six experimental drugs that block TEAD palmitoylation (MGH-CP1, VT-103, VT-107, MSC-4106, MYF-01-37 and K-975). They tested them in malignant pleural mesothelioma cell lines, two with defects in the NF2 gene and two without. VT-103, VT-107 and K-975 slowed growth most in the NF2-defective cells, but none of the drugs stopped growth completely. For most drug and gene pairs, the activity of three target genes fell by less than 50%. The authors then tested VT-103 together with each of 2802 cancer drugs in two NF2-defective cell lines. They identified fifteen groups of drug targets where drugs consistently worked better combined with VT-103, led by glucocorticoid-receptor agonists, MEK1/2 inhibitors and mTOR inhibitors. These combined effects were largely independent of apoptosis (programmed cell death). The authors concluded that the drugs had limited effect on their own. They described the combined effects as mostly growth-stopping rather than cell-killing, which they called a limitation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study in cancer cell lines: drug comparison using cell-based and biochemical assays, plus high-throughput drug-combination screening
• Who was studied: Malignant pleural mesothelioma cell lines bought from ATCC: NCI-H28 and NCI-H2452 (NF2 wild-type), NCI-H226 (NF2-deficient), NCI-H2052 (NF2 mutant) and MSTO-211H (LATS-deficient). The Hippo pathway-proficient cell line HepG2 was also used. No human participants.
• Exposure: Not an asbestos exposure study. Six TEAD auto-palmitoylation inhibitors were tested at 0.1, 1.0 and 10 µM: reversible MGH-CP1, VT-103, VT-107 and MSC-4106, and covalent MYF-01-37 and K-975. VT-103 was then combined with each of 2802 drugs in the MIPE 6.0 oncology library.
• Main results:
  • In the two NF2-defective cell lines, VT-103, VT-107 and K-975 inhibited proliferation most strongly.
  • None of the six inhibitors completely blocked proliferation. At least one population doubling was seen over the 4-day time course.
  • At the 10 µM dose, VT-103, VT-107, K-975 and MGH-CP1 (printed 'MC-CP1') also affected the growth of NF2 wild-type cell lines.
  • For most drug and gene pairs, the inhibitors reduced the expression of the YAP/TEAD target genes by less than 50%.
  • By comparison, CDK9 inhibition with Dinaciclib blocked YAP/TEAD transcriptional output completely (more than 90%).
  • In the combination screen, the most synergistic hits included two MEK inhibitors, with mirdametinib (printed 'Mirdametinb') as the top hit.
  • Fifteen target-level co-dependencies were identified, meaning drug targets whose inhibition consistently synergized with VT-103 (FDR less than 10%).
  • The three most enriched targets for synergy were glucocorticoid receptors, MEK1/2 kinases and mTOR kinases.
  • Some targets worked against VT-103's effects (antagonism), including DHFR and NAMPT inhibitors and modulators of BCL2-family proteins.
  • In the secondary screens, the synergies were largely independent of apoptosis induction.
• The authors' conclusion: The authors concluded that TEAD-palmitoylation inhibitors had overall limited efficacy as single agents in cell line models of pleural mesothelioma. They also concluded that the screen identified several druggable TEAD co-dependencies that could support work on drug-combination strategies.
• Limitations the authors state:
  • None of the drug pairs led to a robust apoptotic response, suggesting the synergies were mostly cytostatic (growth-stopping). The authors called this a limitation from a translational standpoint.
  • A detailed mechanistic understanding of the drug-to-drug interactions was beyond the scope of the work.
  • The authors described their mechanistic understanding of TEAD palmitoylation regulation as partial.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Hippo Signaling Pathway.

Related studies

• Experimental assessment of computationally nominated small molecules targeting the YAP-TEAD interface in Hippo pathway-altered mesothelioma cell models — G.J. Weiss, J.C. Loftus, et al. (2026)
• Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity — A. Gridnev, S. Maity, et al. (2022)
• First-in-human phase Ia study of the covalent TEAD palmitoylation inhibitor BPI-460372 in patients with advanced solid tumors: pharmacokinetics, exposure-limited dosing, and early antitumor activity — H. Liang, Y. Xu, et al. (2026)
• Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma — D.S. Potter, R. Du, et al. (2023)
• Old but gold: the role of drug combinations in improving response to immune check-point inhibitors in thoracic malignancies beyond NSCLC — L. Cantini, F. Pecci, et al. (2021)
• Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers — E.A. Chapeau, L. Sansregret, et al. (2024)

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