The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells.
A549 Cells
Antineoplastic Agents
/ pharmacology
CRISPR-Cas Systems
Carcinoma, Non-Small-Cell Lung
/ metabolism
Cell Nucleus
/ metabolism
Drug Resistance, Neoplasm
Hippo Signaling Pathway
Humans
Lung Neoplasms
/ metabolism
Neoplasm Proteins
/ antagonists & inhibitors
Protein Serine-Threonine Kinases
/ genetics
Signal Transduction
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
26
12
2018
accepted:
13
05
2019
revised:
19
04
2019
pubmed:
14
8
2019
medline:
27
2
2020
entrez:
14
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31406246
doi: 10.1038/s41388-019-0924-1
pii: 10.1038/s41388-019-0924-1
doi:
Substances chimiques
Antineoplastic Agents
0
Neoplasm Proteins
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6801-6817Références
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