Related Experiment Video
Updated: Jul 1, 2025
Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel
Published on: May 14, 2018
YAP/TEAD involvement in resistance to paclitaxel chemotherapy in lung cancer
S Brosseau1,2,3, P Abreu1, C Bouchez1
1U830 INSERM "Cancer, Heterogenity, Instability, Plasticity", Team "Stress and Cancer", Institut Curie Research Centre, 26 rue d'Ulm, 75248 Cedex 05, Paris, France.
Abstract:
The Yes-associated protein (YAP) oncoprotein has been linked to both metastases and resistance to targeted therapy of lung cancer cells. We aimed to investigate the effect of YAP pharmacological inhibition, using YAP/TEA domain (TEAD) transcription factor interaction inhibitors in chemo-resistant lung cancer cells. YAP subcellular localization, as a readout for YAP activation, cell migration, and TEAD transcription factor functional transcriptional activity were investigated in cancer cell lines with up-regulated YAP, with and without YAP/TEAD interaction inhibitors. Parental (A549) and paclitaxel-resistant (A549R) cell transcriptomes were analyzed. The half-maximal inhibitory concentration (IC50) of paclitaxel or trametinib, which are Mitogen-Activated protein kinase and Erk Kinase (MEK) inhibitors, combined with a YAP/TEAD inhibitor (IV#6), was determined. A three-dimensional (3D) microfluidic culture device enabled us to study the effect of IV#6/paclitaxel combination on cancer cells isolated from fresh resected lung cancer samples. YAP activity was significantly higher in paclitaxel-resistant cell lines. The YAP/TEAD inhibitor induced a decreased YAP activity in A549, PC9, and H2052 cells, with reduced YAP nuclear staining. Wound healing assays upon YAP inhibition revealed impaired cell motility of lung cancer A549 and mesothelioma H2052 cells. Combining YAP pharmacological inhibition with trametinib in K-Ras mutated A549 cells recapitulated synthetic lethality, thereby sensitizing these cells to MEK inhibition. The YAP/TEAD inhibitor lowered the IC50 of paclitaxel in A549R cells. Differential transcriptomic analysis of parental and A549R cells revealed an increased YAP/TEAD transcriptomic signature in resistant cells, downregulated upon YAP inhibition. The YAP/TEAD inhibitor restored paclitaxel sensitivity of A549R cells cultured in a 3D microfluidic system, with lung cancer cells from a fresh tumor efficiently killed by YAP/TEAD inhibitor/paclitaxel doublet. Evidence of the YAP/TEAD transcriptional program's role in chemotherapy resistance paves the way for YAP therapeutic targeting.
Insights
Pharmacological inhibition of Yes-associated protein (YAP) and TEAD transcription factors reverses chemotherapy resistance in lung cancer. Targeting YAP/TEAD overcomes paclitaxel resistance and sensitizes cells to MEK inhibitors, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The Yes-associated protein (YAP) oncoprotein is implicated in lung cancer metastasis and resistance to targeted therapies.
- Understanding YAP's role in chemo-resistance is crucial for developing effective lung cancer treatments.
Purpose of the Study:
- To investigate the therapeutic potential of pharmacologically inhibiting YAP/TEA domain (TEAD) interactions in chemo-resistant lung cancer cells.
- To evaluate the impact of YAP inhibition on YAP activity, cell migration, and transcriptional activity in lung cancer models.
Main Methods:
- Utilized YAP/TEAD interaction inhibitors (e.g., IV#6) in lung cancer cell lines with varying YAP expression and chemo-resistance.
- Assessed YAP subcellular localization, cell migration (wound healing assays), and TEAD transcriptional activity.
- Employed transcriptomic analysis, drug sensitivity assays (IC50 determination), and a 3D microfluidic culture system with patient-derived cells.
Main Results:
- YAP activity was significantly elevated in paclitaxel-resistant lung cancer cells.
- YAP/TEAD inhibition reduced YAP activity, nuclear localization, and cell motility in multiple lung cancer and mesothelioma cell lines.
- Combination therapy with a YAP/TEAD inhibitor and MEK inhibitor (trametinib) demonstrated synthetic lethality in K-Ras mutated cells, while the YAP/TEAD inhibitor restored paclitaxel sensitivity in resistant cells, even in a 3D microfluidic system with patient samples.
Conclusions:
- The YAP/TEAD transcriptional program plays a significant role in driving chemotherapy resistance in lung cancer.
- Pharmacological inhibition of YAP/TEAD interactions represents a promising therapeutic strategy to overcome chemo-resistance and enhance treatment efficacy.
- Targeting YAP/TEAD offers a viable approach for developing novel lung cancer therapies, potentially in combination with existing treatments.
Related Concept Videos
01:15Drugs that Stabilize Microtubules
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...