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

Giulia Gobbi, Benedetta Donati, Italo Faria Do Valle, Francesca Reggiani, Federica Torricelli, Daniel Remondini, Gastone Castellani, Davide Carlo Ambrosetti, Alessia Ciarrocchi, Valentina Sancisi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)6801-6817
Number of pages17
JournalOncogene
Volume38
Issue number42
DOIs
Publication statusPublished - Oct 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Gobbi, G., Donati, B., Do Valle, I. F., Reggiani, F., Torricelli, F., Remondini, D., Castellani, G., Ambrosetti, D. C., Ciarrocchi, A., & Sancisi, V. (2019). The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells. Oncogene, 38(42), 6801-6817. https://doi.org/10.1038/s41388-019-0924-1