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G. Woodard
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-016 - Ponatinib Shows Promise in Malignant Pleural Mesothelioma Cells with Abl Pathway Dysregulation (ID 723)
09:30 - 09:30 | Author(s): G. Woodard
- Abstract
Background:
Malignant pleural mesothelioma (MPM) remains a lethal cancer with limited treatment options. Various tyrosine kinases including c-Abl/Arg, FGFR1, Src and PDGFRa/b have been implicated in driving the growth of MPM. Ponatinib is an FDA approved potent multi-target inhibitor of cAbl/Arg, PDGFRα, VEGFR2, FGFR1, and Src. The aim of this study was to investigate the effects of ponatinib on MPM cells.
Methods:
The in vitro effect of ponatinib on different MPM cell lines (H2052, MSTO211H, H2452, H28) were evaluated by MTS assay and the effect on cell migration was determined using a “scratch wound” assay. Levels of phosphorylated-Crkl (pCrkl) were evaluated by western blot and double-strand DNA breaks (DSDBs) measured via the surrogate marker γ-H2AX in an ELISA assay. A xenograft MPM model was used to examine the effects of ponatinib on tumor grown in vivo.
Results:
High levels of pCrkl were expressed in all MPM cell lines studied indicating c-Abl/Arg pathway activation. In vitro, ponatinib was effective against all MPM cell lines by cytotoxicity assay, led to dramatic cell migration inhibition, significantly reduced pCrkl expression, and increased DSDBs. In vivo, ponatinib blunted tumor growth in a xenograft model. Reduced pCrkl levels were observed in xenograft tumor specimens following ponatinib treatment.
Conclusion:
Inhibition of Abl kinase activity with ponatinib is a potential therapeutic approach in MPM patients with Abl pathway dysregulation. pCrkl shows promise as a biomarker of increased Abl kinase activity and may be useful in identifying MPM patients most likely to benefit from ponatinib.
