BAG2, MAD2L1, and MDK are cancer-driver genes and candidate targets for novel therapies in malignant pleural mesothelioma

Luisa Bisceglia, Federica Morani, Lara Guerrieri, Eric Santoni-Rugiu, Pınar Çakılkaya, Cristian Scatena, Rosa Scarpitta, Lars H. Engelholm, Niels Behrendt, Federica Gemignani, Stefano Landi*

*Corresponding author af dette arbejde

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Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and the identification of novel druggable targets is urgently needed. In previous work, we identified 15 deregulated genes highly expressed in MPM tissues and correlated with a poor prognosis. Here, we validated these findings on an independent dataset of 211 MPM patients (EGA, EGAD00001001915) and on a panel of MPM cell lines. Furthermore, we carried out in vitro gene silencing followed by proliferation, cytotoxicity, caspase, and migration assays to define whether these targets could be cancer-driver genes. We ended up with three novel candidates (i.e., BAG2, MAD2L1, and MDK), whose encoded proteins could be exploited as druggable targets. Moreover, of novelty, immunohistochemistry analysis on tissues revealed that the overexpression of BAG2 and MAD2L1 could differentiate MPM from RMP patients. Furthermore, when we tested Neratinib (an inhibitor of MAD2L1) and iMDK (an inhibitor of MDK) we found that they are effective on MPM cells, in part phenocopying the effects of MAD2L1 and MDK gene silencing. In summary, in the present work, we report that BAG2, MAD2L1, and MDK are bona fide cancer-driver genes for MPM worth of further studies.
OriginalsprogEngelsk
TidsskriftCancer Gene Therapy
Vol/bind31
Udgave nummer11
Sider (fra-til)1708-1720
Antal sider13
ISSN0929-1903
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
This work was supported by Associazione Italiana per la Ricerca sul Cancro AIRC IG 2018 Id. 21853 (SL), by the Research Grant from the Ministery of the University and Research (MIUR), Department of Excellence 2023-2027 (SL, FG), by the European Union\u2019s Horizon 2020 research and innovation program under the Marie Sk\u0142odowska-Curie Grant Agreement No. 801481 (P\u00C7), the Novo Nordisk Foundation Grant No. NNF19OC0058603 (NB), the Danish Cancer Society Grant No. R231-A13820 (NB) and R231-A13832 (LHE), the Research Foundation of the Danish Capital Region (Region Hovedstadens Forskningsfond) (NB) and Simon Fougner Hartmanns family foundation (LHE). The Department of Biology of University of Pisa contributed for the publication fees.

Publisher Copyright:
© The Author(s) 2024.

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