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- W3207748610 abstract "Malignant pleural mesothelioma (MPM) is a rare cancer that afflicts ∼3,200 new patients per year in the US and 25,576 deaths were reported worldwide in 2018. Currently there are no targeted therapies approved for MPM. Approximately 80-85% of MPM bear wild-type (WT) TP53, a key tumor suppressor subject to ubiquitylation and degradation via the E3 ligase, MDM2. Furthermore, p14ARF, a critical negative regulator of MDM2 encoded by the CDKN2A gene, is lost in up to 80% of MPM via deletion or methylation of CDKN2A. MDM2 inhibitors have been developed that result in increased p53 function to yield growth inhibition or apoptosis of tumor cells. The fact that the majority of MPM tumors bear WT TP53 and p14ARF/CDKN2A loss suggests a potential vulnerability that may be amenable to precision oncology strategies utilizing MDM2 inhibitors. A panel of six human mesothelioma cell lines (H28, H226, H290, H2052, H2452, MSTO211H) with defined TP53 and MDM2 status were submitted to in vitro clonogenic growth assays and immunoblot analyses with MDM2 inhibitors RAIN-32 (milademetan) and KRT-232 (AMG-232). Two MDM2 inhibitor-sensitive MPM cell lines (MSTO211H and H226) were propagated as flank xenografts in nu/nu mice and sensitivity to oral dosing with RAIN-32 was determined. TableCell LineH28H226H290H2052H2452MSTO211HRAIN-32 IC50, nM32.025.019.19.57,448.05.5KRT-232 IC50, nM54.8103.0102.775.36,333.024.4TP53 statusWTWTWTWTWT, lo mRNAWTTP53 mRNA, rel. exp.0.8391.0471.1000.5540.0000.326CDKN2A statusDel--deldeldelCDKN2A mRNA, rel. exp.0.00000.00330.00000.00000.00020.0047MDM2 mRNA, rel. exp.0.570.480.960.940.100.51 Open table in a new tab The IC50 values for RAIN-32 and KRT-232 ranged from 6 - 32 nM and 24 -103 nM, respectively, in the 5 MPM cell lines bearing WT TP53, but was greater than 5 mM in H2452 cells which lack TP53 mRNA expression (see Table). Notably, the status of CDKN2A encoding the p16 cyclin-dependent kinase inhibitor and p19 ARF was null in all of the lines with undetectable mRNA levels observed. Moreover, RAIN-32 treatment (24 hr) increased p53 protein levels in the MDM2 inhibitor-sensitive lines as well as PARP cleavage. Daily oral dosing with RAIN-32 at 50 mg/kg significantly reduced the growth of both MSTO211H and H226 flank xenografts. MDM2 inhibitors selectivity and potently inhibit in vitro and in vivo growth of MPM cell lines bearing WT TP53. In light of the fact that there are no approved therapies following MPM treatment failure with standard cytotoxic agents or anti-PD1-based immunotherapy, the MDM2/p53 axis represents an attractive target for further clinical exploration in this disease." @default.
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- W3207748610 date "2021-10-01" @default.
- W3207748610 modified "2023-09-25" @default.
- W3207748610 title "FP07.01 The MDM2/p53 Axis is a Therapeutic Vulnerability in Malignant Pleural Mesothelioma" @default.
- W3207748610 doi "https://doi.org/10.1016/j.jtho.2021.08.226" @default.
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