Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf
| Autor: | Vincent Romanet, Marion Wiesmann, Roland Rad, Eric Durand, William R. Sellers, Audrey Kauffmann, Sébastien Jeay, Francesco Hofmann, Armelle Grevot, Agnieszka Gembarska, Antoine de Weck, Emeline Mandon, Ralph Tiedt, Louise Barys, Esther Sutter, Michael Rugaard Jensen, Stephane Ferretti, Masato Murakami, Pierre Moulin, Joseph Lehar, Emilie A. Chapeau, Claire Estadieu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Transposable element Somatic cell Genetic Vectors bcl-X Protein Mutagenesis (molecular biology technique) Antineoplastic Agents Kaplan-Meier Estimate Insertional mutagenesis 03 medical and health sciences Mice p14arf Neoplasms Biomarkers Tumor Animals Humans neoplasms Gene Mice Knockout Multidisciplinary biology Genetic Drift Wild type Proto-Oncogene Proteins c-mdm2 Biological Sciences Allografts Molecular biology Disease Models Animal Mutagenesis Insertional 030104 developmental biology Cell Transformation Neoplastic Drug Resistance Neoplasm biology.protein DNA Transposable Elements Mdm2 Tumor Suppressor Protein p53 |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 114(12) |
| ISSN: | 1091-6490 |
| Popis: | Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which 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 used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB 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 the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposon-mediated gain-of-function alterations in B-cell lymphoma-extra large (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 protein 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. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy. |
| Databáze: | OpenAIRE |
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