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The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells

Oncogene volume 38, pages 6801–6817 (2019)Cite this article

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Abstract

Inhibitors of BET proteins (BETi) are anti-cancer drugs that have shown efficacy in pre-clinical settings and are currently in clinical trials for different types of cancer, including non-small cell lung cancer (NSCLC). Currently, no predictive biomarker is available to identify patients that may benefit from this treatment. To uncover the mechanisms of resistance to BETi, we performed a genome-scale CRISPR/Cas9 screening in lung cancer cells. We identified three Hippo pathway genes, LATS2, TAOK1, and NF2, as key determinants for sensitivity to BETi. The knockout of these genes induces resistance to BETi, by promoting TAZ nuclear localization and transcriptional activity. Conversely, TAZ expression promotes resistance to these drugs. We also showed that TAZ, YAP, and their partner TEAD are direct targets of BRD4 and that treatment with BETi downregulates their expression. Noticeably, molecular alterations in one or more of these genes are present in a large fraction of NSCLC patients and TAZ amplification or overexpression correlates with a worse outcome in lung adenocarcinoma. Our data define the central role of Hippo pathway in mediating resistance to BETi and provide a rationale for using BETi to counter-act YAP/TAZ-mediated pro-oncogenic activity.

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Acknowledgements

We want to thank Marina Grassi for technical support and Mauro Mason for support on graphic design. GG is a student of the PhD program in Cellular and Molecular Biology at University of Bologna, Bologna, Italy.

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Author notes

  1. These authors contributed equally: Giulia Gobbi, Benedetta Donati, Italo Faria Do Valle

Authors and Affiliations

  1. Laboratory of Translational Research, Azienda USL di Reggio Emilia – IRCCS, Reggio Emilia, Italy

    Giulia Gobbi, Benedetta Donati, Francesca Reggiani, Federica Torricelli, Alessia Ciarrocchi & Valentina Sancisi

  2. Department of Physics, Center for Complex Network Research, Northeastern University, Boston, MA, USA

    Italo Faria Do Valle

  3. Department of Physics and Astronomy, University of Bologna, Bologna, Italy

    Daniel Remondini & Gastone Castellani

  4. Department of Pharmacy and Biotechnologies (FaBit), University of Bologna, Bologna, Italy

    Davide Carlo Ambrosetti

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Conceptualization: VS and AC; Investigation: GG, BD, FR, FT, DCA, and VS; Methodology; GG, BD, IFV, FT, and VS; Data analysis: IFV, DR, and GC; Writing and reviewing the paper: VS, DCA, and AC.

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Correspondence to Valentina Sancisi.

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Gobbi, G., Donati, B., Do Valle, I.F. et al. The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells. Oncogene 38, 6801–6817 (2019). https://doi.org/10.1038/s41388-019-0924-1

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