Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype

Our plain-English summary of Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype, by X. Ning, T.T.T. Nguyễn, T. Morinaga, et al (PloS One, 2026).

The study

• Authors: X. Ning, T.T.T. Nguyễn, T. Morinaga, Y. Tada, H. Shimada, K. Hiroshima, N. Yamaguchi, M. Tagawa
• Journal: PloS One
• Published: 2026;21(2):e0343551
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma has characteristic genetic changes including inactivation of neurofibromatosis type 2 (NF2) and deletion of the INK4A/ARF region. Cells deficient of NF2 protein (MERLIN) depend on focal adhesion kinase (FAK) for cell adhesion and FAK inhibitors suppress the cell growth. The INK4A/ARF deletion activates MDM2 functions which ubiquitinate and degrade p53, and consequently the cellular p53 levels decrease. The deletion therefore induces loss of p53 functions although a majority of mesothelioma has wild-type TP53 genotype. An MDM2 inhibitor which blocked the ubiquitination increased p53 levels, restored p53 functions and facilitated cell growth arrest. Moreover, FAK and p53 expressions were reciprocally regulated. We examined growth suppressive effects of a FAK inhibitor, defactinib, and MDM2 inhibitors, nutlin-3a and reactivation of p53 and induction of tumor cell apoptosis (RITA), with representative wild-type and mutated TP53 mesothelioma and investigated molecular changes induced by the agents. We analyzed possible combinatory effects of the inhibitors and molecular changes caused by the combination. Our study showed that defactinib inhibited cell growth and induced FAK dephosphorylation irrespective of the TP53 genotype, and that the inhibited FAK phosphorylation was not associated with MERLIN levels or with p53 up-regulation, but linked with AKT dephosphorylation. Nutlin-3a preferentially suppressed growth of wild-type TP53 cells and augment p53 expression without DNA damage, whereas RITA-mediated p53 up-regulation was linked with the damage. A combination of defactinib and the MDM2 inhibitors showed that nutlin-3a showed synergistic/additive effects in wild-type and antagonistic effects in mutated TP53 cells, whereas RITA retained synergistic activity in mutated TP53 cells. These results suggest that the therapeutic success of combined FAK and MDM2 inhibition in mesothelioma depends on the precise matching of MDM2 inhibitors with the TP53 genotypes, and highlight the need for genotype-based selection of MDM2 inhibitors.

Copyright: © 2026 Ning et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

In plain English

This laboratory study used human mesothelioma cell lines grown in dishes; it did not involve patients or asbestos exposure. The authors tested defactinib, which blocks a protein called FAK, and nutlin-3a and RITA, which block MDM2. Each was tested alone and in combination on eight mesothelioma cell lines with normal ('wild-type') or mutated TP53 genes. Defactinib slowed growth similarly regardless of TP53 type or levels of a protein called MERLIN. Nutlin-3a worked better on most wild-type cells than on mutated or non-functional p53 cells. RITA sensitivity varied by cell line but was not associated with TP53 type; the wild-type line EHMES-10 resisted both MDM2 inhibitors. Combined with defactinib, nutlin-3a gave synergistic or additive effects in nutlin-sensitive wild-type cells but antagonistic effects in mutated cells. With defactinib plus RITA, combination index values at 25% to 75% growth suppression were near or below 1 (synergy or additive) in all lines except NCI-H226 and NCI-H2452, which mostly showed antagonism. The authors concluded that the combined effect depended on TP53 status and the MDM2 inhibitor used. They called the work a preclinical proof-of-concept.

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 of human mesothelioma cell lines; the authors call it a preclinical proof-of-concept study
• Who was studied: Eight human mesothelioma cell lines (NCI-H28, MSTO-211H, NCI-H2052, NCI-H226, NCI-H2452, EHMES-10, EHMES-1, JMN-1B), plus immortalized mesothelium-derived Met-5A cells. EHMES-1 and JMN-1B had mutated TP53. The others had wild-type TP53, although NCI-H2452 made a truncated p53 protein.
• Exposure: No asbestos or fiber exposure was studied. The cells were treated for 72 hours with the FAK inhibitor defactinib, the MDM2 inhibitors nutlin-3a and RITA, or combinations of two agents.
• Main results:
  • Sensitivity to defactinib did not differ by TP53 status. The half-maximal inhibitory concentration (IC50) averaged 3.85 plus or minus 0.65 μM in wild-type TP53 cells and 4.52 plus or minus 1.17 in mutated or non-functional p53 cells (P = 0.64).
  • Sensitivity to defactinib was unrelated to MERLIN levels. The IC50 was 5.98 plus or minus 1.00 in MERLIN-high cells and 3.47 plus or minus 0.85 in MERLIN low or negative cells (P = 0.105).
  • Defactinib did not induce apoptotic cell death in most of the cells tested.
  • Nutlin-3a worked better on wild-type TP53 cells (excluding EHMES-10), with an IC50 of 3.62 plus or minus 1.04 μM. Mutated and non-functional p53 cells had an IC50 of 33.5 plus or minus 2.80 (P less than 0.01).
  • Nutlin-3a raised p53 levels apparently without DNA damage, whereas DNA damage responses appeared to contribute to RITA's p53 increase.
  • RITA IC50 values did not differ between wild-type cells excluding EHMES-10 (2.50 plus or minus 1.88 μM) and mutated or non-functional p53 cells (1.67 plus or minus 1.21) (P = 0.73).
  • The wild-type TP53 line EHMES-10, which was excluded from those group comparisons, was resistant to both RITA and nutlin-3a.
  • Sensitivity to RITA depended on the cell line and was not associated with TP53 genotype or p53 functional status.
  • Defactinib plus nutlin-3a gave synergistic or additive growth inhibition in nutlin-3a-sensitive wild-type TP53 cells, but antagonistic effects in mutated TP53 cells.
  • For defactinib plus RITA, combination index values at fractions affected between 0.25 and 0.75 were below or about 1 in all cells except NCI-H226 and NCI-H2452. Most values in those two lines were above 1. Values below 1 indicate synergy, about 1 additive, and above 1 antagonism.
• The authors' conclusion: The authors concluded that combining defactinib with an MDM2 inhibitor produced synergistic or additive growth inhibition in a way determined by TP53 status and by which MDM2 inhibitor was used.
• Limitations the authors state:
  • The authors did not precisely examine whether defactinib induces DNA damage.
  • The reason EHMES-10 cells resisted nutlin-3a is unknown.
  • It remains unknown whether RITA-induced DNA damage directly influenced FAK activity.
  • The authors noted that sensitivity to FAK inhibitors depends on many factors, including the experimental system used in the lab and the local environment in the body.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Merlin, Apoptosis.

Related studies

• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression — T.T.T. Nguyen, M. Shingyoji, et al. (2021)
• HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN, irrespective of p53 mutational status — W.B. Ou, J. Zhu, et al. (2015)
• Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma — R. Kanteti, T. Mirzapoiazova, et al. (2018)
• The p53/mouse double minute 2 homolog complex deregulation in merlin-deficient tumours — S. Ammoun, M.C. Schmid, et al. (2015)
• Combined use of irinotecan and p53 activator enhances growth inhibition of mesothelioma cells — B. Han, H.C. Lee-Okada, et al. (2020)

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