The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells
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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- Authors
- Gobbi, G., Donati, B., Do Valle, I. F., Reggiani, F., Torricelli, F., Remondini, D., Castellani, G., Ambrosetti, D. C., Ciarrocchi, A., & Sancisi, V.
- Affiliations
- Azienda Sanitaria Unità Locale di Reggio Emilia (IT)
- University of Bologna (IT)
- Corresponding author
- Sancisi, Valentina
- ORCID
- Venue
- Oncogene
- Published
- 2019-08-12
- Volume
- 38
- Issue
- 42
- Pages
- 6801-6817
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2967319134
- Cited by
- 69
- References
- 50
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 14 · 2022: 10 · 2021: 15 · 2020: 15 · 2019: 3
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- Hippo signaling pathway, BET inhibitors, drug resistance, non-small cell lung cancer, TAZ, YAP, TEAD, LATS2, TAOK1, neurofibromatosis type 2, BRD4, CRISPR-Cas9 screen, lung adenocarcinoma, predictive biomarkers
- MeSH terms
- A549 Cells, Hippo Signaling Pathway, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Nucleus, Humans, Lung Neoplasms, Neoplasm Proteins, Signal Transduction, Protein Serine-Threonine Kinases, Drug Resistance, Neoplasm, CRISPR-Cas Systems
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