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- W2885205861 abstract "Inhibitors of MDM2-TP53 interaction are predicted to be effective in tumors where the TP53 gene is wild-type by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we utilized piggyBac transposon insertional mutagenesis to anticipate resistance mechanisms that occur under intermittent high dose treatment with the MDM2-TP53 inhibitor HDM201. Constitutive piggyBac mutagenesis in Arf-/- mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess HDM201 pharmacological effects. 16 out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. When tumors with acquired resistance to HDM201 were compared to untreated tumors, 87 genes were found differentially and significantly targeted by piggyBac transposon. Resistant tumors displayed a complex clonality pattern suggesting emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in Trp53 in 54% of tumors, and transposon-mediated gain-of-function alterations in Bcl-xL, Mdm4, and two TP53-family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 proteins expression was confirmed in resistant tumors, as well as in HDM201 resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Moreover, we performed an additional piggyBac screen with daily HDM201 treatment, at lower dose. Surprisingly, we identified Bcl-XL expression as a unique mechanism of resistance in intermittent high dose scheduling. These data suggested that different apoptotic inductions between the two HDM201 dose regimens (intermittent high dose/daily lower dose) likely play a role in the way the resistance to HDM201 takes place. Collectively, our study has identified several potential mechanisms by which TP53 wild-type tumors may escape MDM2 targeted therapy, and provide evidence that Bcl-XL inhibition may be beneficial for relapsing patients that were treated with HDM201 intermittent scheduling. Citation Format: Emilie A. Chapeau. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5908." @default.
- W2885205861 created "2018-08-22" @default.
- W2885205861 creator A5083228866 @default.
- W2885205861 date "2018-07-01" @default.
- W2885205861 modified "2023-09-25" @default.
- W2885205861 title "Abstract 5908: Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen" @default.
- W2885205861 doi "https://doi.org/10.1158/1538-7445.am2018-5908" @default.
- W2885205861 hasPublicationYear "2018" @default.
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