Ponatinib is a potential therapeutic approach for malignant pleural mesothelioma

Our plain-English summary of Ponatinib is a potential therapeutic approach for malignant pleural mesothelioma, by Y.W. Yang, A. Marrufo, J. Chase, et al (Experimental Lung Research, 2021).

The study

• Authors: Y.W. Yang, A. Marrufo, J. Chase, G.A. Woodard, D.M. Jablons, H. Lemjabbar-Alaoui
• Journal: Experimental Lung Research
• Published: 2021;47(1):9-25
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Malignant pleural mesothelioma (MPM) is a rare and deadly malignancy. Current MPM therapies remain inadequate, and outcomes are often disappointing. New meaningful therapeutic approaches are urgently needed. Accumulating evidence indicates that the cAbl pathway promotes various tumor-stimulating processes in MPM. In this study, we sought to determine ponatinib's potential utility, a clinically approved and potent cAbl inhibitor, in MPM treatment.

Material And Methods: Four MPM lines (MSTO211H, H28, H2452, H2052) were treated with ponatinib in vitro, and their growth was assessed. Scratch wound assay was used to investigate the ponatinib effect on cell migration. The expression levels of pAbl and its downstream effectors pCrkL, pAKT, and pSTAT5 were characterized. The in vivo ponatinib effect was evaluated in human MPM cells derived tumor model.

Results: In all four MPM lines, significant expression levels of phosphorylated cAbl/Arg and pCrkl were observed. Differentially but strongly, ponatinib inhibited the in vitro cell growth and migration of all four MPM line. Western blot analysis showed that the activation of Abl signaling was blocked in the ponatinib-treated MMP lines. In keeping, the cellular levels of pAbl and its downstream effector pCrkL, pAKT, and pSTAT5 were markedly decrease following ponatinib treatment. Moreover, ponatinib treatment amplified the levels of γH2AX in cells denoting increased double-strand DNA breaks levels. Notably, ponatinib treatment reduced in vivo tumor growth and reduced pCrkl and pSTAT5 levels in tumor samples.

Conclusion: Ponatinib may offer a new therapeutic strategy for MPM patients based on cAbl signaling pathway inhibition.

In plain English

This laboratory study in cultured cells and mice tested whether ponatinib, a leukemia drug that blocks a protein called cAbl, might act against malignant pleural mesothelioma. It did not study asbestos exposure, and no patients were treated. Public gene data showed cAbl about four times higher in mesothelioma than in normal lung, and all 10 archived UCSF tumors stained for cAbl. In four mesothelioma cell lines, ponatinib slowed growth, with concentrations halving growth between 90 and 200 nM. The two lines classed as epithelial were more sensitive than the two biphasic lines. It reduced cAbl signaling in all four lines and slowed cell movement in the two lines tested. It also raised a DNA-break marker in MSTO-211H, the only line tested for it. In mice with human mesothelioma tumors (5 per group), ponatinib slowed tumor growth compared with mice given drug-free liquid. In MSTO-211H cells only, ponatinib with cisplatin was synergistic at some combination ratios. No significant synergy or additive effect was seen with pemetrexed or gemcitabine at the ratios tested. The authors concluded their results suggest a potential use for ponatinib in mesothelioma patients.

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 (preclinical) study. It combined experiments on human mesothelioma cell lines, a mouse xenograft experiment, staining of archived human tumors, and mining of public gene-expression data. No patients were treated.
• Who was studied: Four human malignant pleural mesothelioma cell lines: MSTO-211H and H2452, described as epithelial, and H28 and H2052, described as biphasic. The study also used 10 archived surgical tumor specimens from UCSF and female immunodeficient (NSG) mice, 5 per treatment group. Public microarray data covered 4 normal lung, 5 normal pleura and 40 mesothelioma samples.
• Exposure: The drug ponatinib, a cAbl inhibitor, compared with vehicle (drug-free) control. Cells received a range of concentrations, and mice received 30 mg/kg by mouth. In MSTO-211H cells it was also tested in combination with cisplatin, pemetrexed and gemcitabine. Asbestos exposure was not studied; asbestos appears only in the introduction's background.
• Main results:
  • In public microarray data, cAbl gene expression was about four-fold higher in mesothelioma than in normal tissue (P = 0.001).
  • All 10 archived human mesothelioma tumors showed varying degrees of cAbl staining in the tumor cells.
  • Ponatinib inhibited growth of all four cell lines in a dose-dependent way. The concentration inhibiting 50% of growth (IC50) ranged between 90 and 200 nM.
  • Ponatinib was more effective in the epithelial-subtype lines (MSTO-211H, H2452) than in the biphasic-subtype lines (H2052, H28).
  • At 24 hours, ponatinib inhibited scratch-wound recovery, a measure of cell migration, in both lines tested (MSTO-211H and H28), with p less than 0.05.
  • In the four cell lines, ponatinib reduced active (phosphorylated) cAbl in a dose-dependent way. It also reduced phosphorylated CrkL and Akt.
  • In MSTO-211H cells, the only line tested for this, ponatinib produced a dose-dependent increase in gamma-H2AX, a marker of double-strand DNA breaks.
  • In MSTO-211H and H28 cells, ponatinib inhibited EGFR and HGFR activation. In H28 cells it mildly increased Axl kinase activity.
  • In mice with MSTO-211H-derived tumors (5 per group), ponatinib inhibited tumor growth compared with vehicle-treated mice. It also reduced pCrkl and pSTAT5 levels in the tumors.
  • In MSTO-211H cells, ponatinib combined with cisplatin gave synergistic cytotoxicity at some combination ratios.
  • In MSTO-211H cells, combinations of ponatinib with pemetrexed or gemcitabine showed no significant synergistic or additive effect at the combination ratios tested. These data were not shown.
• The authors' conclusion: The authors concluded that their results suggest a potential use for ponatinib in mesothelioma patients through inhibition of cAbl kinase. They saw their findings as a rationale for a new translational therapeutic approach.
• Limitations the authors state:
  • The authors stated it is not clear whether the changes in receptor tyrosine kinases caused by ponatinib were sequential or simultaneous, or primary or secondary effects. It is also unclear how they affect the drug's toxicity to mesothelioma cells; further investigation is needed.
  • The study did not reproduce an earlier report of FGFR1 expression in MSTO-211H cells. The authors said the difference could be due to assay conditions or experiment design.
  • The authors stated that the role of Axl in mesothelioma cells' sensitivity to ponatinib needs further investigation.

Topics

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

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

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• KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma — S. Cregan, L. McDonagh, et al. (2016)
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• p90 ribosomal S6 kinase: a potential therapeutic target in lung cancer — N. Poomakkoth, A. Issa, et al. (2016)

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