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Updated: Dec 3, 2025
Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
Ponatinib is a potential therapeutic approach for malignant pleural mesothelioma
Yi-Wei Yang1, Angelica Marrufo1, Jillian Chase1
1Department of Surgery, Thoracic Oncology Program, University of California, San Francisco, San Francisco, California, USA.
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.
Insights
Ponatinib effectively inhibited malignant pleural mesothelioma (MPM) cell growth and migration by blocking the cAbl pathway. This study suggests ponatinib as a promising new therapy for MPM patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer with limited treatment options.
- Current therapies for MPM are inadequate, necessitating novel therapeutic strategies.
- The cAbl signaling pathway is implicated in promoting tumor progression in MPM.
Purpose of the Study:
- To investigate the therapeutic potential of ponatinib, a cAbl inhibitor, for treating MPM.
- To assess the efficacy of ponatinib in inhibiting MPM cell growth and migration.
- To evaluate the impact of ponatinib on cAbl pathway activation and downstream signaling in MPM.
Main Methods:
- In vitro treatment of four MPM cell lines with ponatinib.
- Assessment of cell growth and migration using scratch wound assays.
- Western blot analysis to characterize protein expression of pAbl, pCrkL, pAKT, and pSTAT5.
- In vivo evaluation of ponatinib efficacy in a human MPM xenograft model.
Main Results:
- Ponatinib significantly inhibited in vitro growth and migration of all tested MPM cell lines.
- Ponatinib blocked Abl signaling activation, reducing levels of pAbl, pCrkL, pAKT, and pSTAT5.
- Increased double-strand DNA breaks (γH2AX) were observed following ponatinib treatment.
- In vivo studies showed reduced tumor growth and decreased pCrkL and pSTAT5 levels in ponatinib-treated tumors.
Conclusions:
- Ponatinib demonstrates significant anti-tumor activity against MPM in vitro and in vivo.
- Inhibition of the cAbl signaling pathway by ponatinib is a viable therapeutic strategy for MPM.
- Ponatinib represents a promising new therapeutic option for patients with malignant pleural mesothelioma.
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