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

Our plain-English summary of 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, by B. Zhong, M. Shingyoji, M. Hanazono, et al (Apoptosis, 2020).

The study

• Authors: B. Zhong, M. Shingyoji, M. Hanazono, T.T. Nguyễn, T. Morinaga, Y. Tada, H. Shimada, K. Hiroshima, M. Tagawa
• Journal: Apoptosis
• Published: 2020;25(7-8):535-547
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

A majority of mesothelioma had the wild-type p53 genotype but was defective of p53 functions primarily due to a genetic defect in INK4A/ARF region. We examined a growth suppressive activity of CP-31398 which was developed to restore the p53 functions irrespective of the genotype in mesothelioma with wild-type or mutated p53. CP-31398 up-regulated p53 levels in cells with wild-type p53 genotype but induced cell growth suppression in a p53-independent manner. In contrasts, nutlin-3a, an MDM2 inhibitor, increased p53 and p21 levels in mesothelioma with the wild-type p53 genotype and produced growth suppressive effects. We investigated a combinatory effect of CP-31398 and nutlin-2a and found the combination produced synergistic growth inhibition in mesothelioma with the wild-type p53 but not with mutated p53. Western blot analysis showed that the combination increased p53 and the phosphorylation levels greater than treatments with the single agent, augmented cleavages of PARP and caspase-3, and decreased phosphorylated FAK levels. Combination of CP-31398 and defactinib, a FAK inhibitor, also achieved synergistic inhibitory effects and increased p53 with FAK dephosphorylation levels greater than the single treatment. These data indicated that a p53-activating CP-31398 achieved growth inhibitory effects in combination with a MDM2 or a FAK inhibitor and suggested a possible reciprocal pathway between p53 elevation and FAK inactivation.

In plain English

This laboratory study used cultured cells, not patients, and did not study asbestos. The authors tested CP-31398, an experimental compound meant to restore the tumor-suppressor protein p53. They compared cell lines with a wild-type p53 gene against a 'p53-mutated group'. That group also included NCI-H2452 (wild-type gene, shortened p53 protein) and Met-5A mesothelial cells (p53 inactivated by a viral protein). CP-31398 slowed growth similarly in both groups (average half-maximal inhibitory concentration 7.51 µM wild-type, 5.57 µM p53-mutated; P = .15). Nutlin-3a, which blocks a protein called MDM2, was more effective in wild-type cells, excluding EHMES-10 (3.64 µM), than in the p53-mutated group (30.49 µM). CP-31398 plus nutlin-3a was synergistic in wild-type cells. In the p53-mutated group it was rather antagonistic at most points measured under a high nutlin-3a concentration. CP-31398 plus defactinib, which blocks a protein called FAK, was also synergistic in MSTO-211H and NCI-H28 cells. The authors concluded that pairing a p53-activating agent with an MDM2 or a FAK inhibitor is a therapeutic option for mesothelioma. Neither pairing was tested in patients. They noted that the drugs' mechanisms need detailed analysis.

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) experiment on human mesothelioma cell lines grown in culture
• Who was studied: Human mesothelioma cell lines and immortalized Met-5A mesothelial cells. Wild-type p53 group: MSTO-211H, NCI-H28, NCI-H226, NCI-H2052 and EHMES-10. The 'p53-mutated group' contained JMN-1B and EHMES-1, which have a mutated genotype. It also contained NCI-H2452, which has a wild-type genotype but expresses a truncated p53 protein, and Met-5A, which expresses p53-inactivating SV40 T antigen. JMN-1B, EHMES-1 and EHMES-10 were established from Japanese patients.
• Exposure: Drug treatments in the laboratory, not asbestos: CP-31398 (a p53-activating compound), nutlin-3a (an MDM2 inhibitor) and defactinib (a FAK inhibitor), used alone and in two-drug combinations with CP-31398
• Main results:
  • CP-31398 growth inhibition did not differ by p53 genotype: average IC50 was 7.51 ± 1.06 µM for wild-type p53 cells and 5.57 ± 0.11 for the p53-mutated group (P = .15). The p53-mutated group included NCI-H2452 and Met-5A.
  • Nutlin-3a was more effective in wild-type p53 cells, excluding EHMES-10 (average IC50 3.64 ± 2.87 µM), than in the p53-mutated group (30.49 ± 7.93), P < .01
  • CP-31398 plus nutlin-3a was synergistic in wild-type p53 mesothelioma cells. In mutated p53 cells it was not synergistic. It was rather antagonistic at a majority of Fa points (fractions of cells affected) under a high concentration of nutlin-3a.
  • In cell cycle analysis, the combination increased the sub-G1 (dying cell) fraction in MSTO-211H cells but not in NCI-H28 cells. The authors read this as cell death in MSTO-211H and cell cycle arrest in NCI-H28.
  • CP-31398 plus defactinib produced synergistic growth inhibition in MSTO-211H and NCI-H28 cells
• The authors' conclusion: The authors reported that CP-31398 achieved synergistic effects with nutlin-3a or with defactinib, each tested separately in cells. They concluded that an MDM2 inhibitor and a FAK inhibitor are potential therapeutic agents for mesothelioma, and that using such an inhibitor with a p53-activating agent is a therapeutic option. They also reported that p53 expression and FAK phosphorylation appeared to be reciprocally regulated.
• Limitations the authors state:
  • The authors stated that the mechanism of the drug actions requires detailed analysis
  • The authors stated that the mechanism by which p53 regulates FAK phosphorylation was not well understood
  • The authors stated that why EHMES-10 cells resisted nutlin-3a remained uncharacterized

Topics

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

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