The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells
| Autor: | Benedetta Donati, Daniel Remondini, Francesca Reggiani, Federica Torricelli, Valentina Sancisi, Italo Faria do Valle, Gastone Castellani, Alessia Ciarrocchi, Davide Ambrosetti, Giulia Gobbi |
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| Přispěvatelé: | Gobbi G., Donati B., Do Valle I.F., Reggiani F., Torricelli F., Remondini D., Castellani G., Ambrosetti D.C., Ciarrocchi A., Sancisi V. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research BRD4 Lung Neoplasms Antineoplastic Agents Drug resistance Protein Serine-Threonine Kinases Biology 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Genetics medicine Humans Hippo Signaling Pathway Lung cancer Molecular Biology Cell Nucleus A549 cell Hippo signaling pathway Cancer medicine.disease Neoplasm Proteins Hippo pathway BETi BRD4 CRISPR/Cas9 screening NSCLC 030104 developmental biology A549 Cells Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Adenocarcinoma CRISPR-Cas Systems Nuclear localization sequence Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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