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GSK2801 Reverses Paclitaxel Resistance in Anaplastic Thyroid Cancer Cell Lines through MYCN Downregulation
Elisabetta Molteni1, Federica Baldan1,2, Giuseppe Damante1,2
1Department of Medicine, University of Udine, Via Chiusaforte, 33100 Udine, Italy.
Abstract:
Anaplastic thyroid cancer (ATC) is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. Treatment with taxanes (such as paclitaxel) is an important approach in counteracting ATC or slowing its progression in tumors without known genetic aberrations or those which are unresponsive to other treatments. Unfortunately, resistance often develops and, for this reason, new therapies that overcome taxane resistance are needed. In this study, effects of inhibition of several bromodomain proteins in paclitaxel-resistant ATC cell lines were investigated. GSK2801, a specific inhibitor of BAZ2A, BAZ2B and BRD9, was effective in resensitizing cells to paclitaxel. In fact, when used in combination with paclitaxel, it was able to reduce cell viability, block the ability to form colonies in an anchor-independent manner, and strongly decrease cell motility. After RNA-seq following treatment with GSK2801, we focused our attention on MYCN. Based on the hypothesis that MYCN was a major downstream player in the biological effects of GSK2801, we tested a specific inhibitor, VPC-70619, which showed effective biological effects when used in association with paclitaxel. This suggests that the functional deficiency of MYCN determines a partial resensitization of the cells examined and, ultimately, that a substantial part of the effect of GSK2801 results from inhibition of MYCN expression.
Insights
New research shows inhibiting bromodomain proteins, specifically BAZ2A/B and BRD9, can resensitize anaplastic thyroid cancer (ATC) cells to paclitaxel. This approach targets MYCN, offering a potential strategy against taxane resistance in this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Anaplastic thyroid cancer (ATC) is a rare and highly aggressive malignancy with a poor prognosis.
- Taxane chemotherapy (e.g., paclitaxel) is a key treatment for ATC, but resistance frequently develops, necessitating novel therapeutic strategies.
- Bromodomain proteins play roles in gene regulation and are implicated in various cancers, making them potential therapeutic targets.
Purpose of the Study:
- To investigate the efficacy of inhibiting specific bromodomain proteins in overcoming paclitaxel resistance in anaplastic thyroid cancer cells.
- To identify downstream molecular mechanisms, particularly MYCN, involved in the therapeutic effects of bromodomain inhibition.
Main Methods:
- Utilized paclitaxel-resistant ATC cell lines.
- Administered GSK2801, a specific inhibitor of BAZ2A, BAZ2B, and BRD9.
- Assessed cell viability, colony formation, and cell motility in combination treatments.
- Performed RNA sequencing (RNA-seq) to analyze gene expression changes.
- Tested VPC-70619, a MYCN inhibitor, in combination with paclitaxel.
Main Results:
- GSK2801 treatment resensitized paclitaxel-resistant ATC cells.
- Combination therapy with GSK2801 and paclitaxel reduced cell viability, inhibited colony formation, and decreased cell motility.
- RNA-seq analysis identified MYCN as a potential downstream target of GSK2801.
- Inhibition of MYCN with VPC-70619 partially resensitized cells to paclitaxel, suggesting MYCN's role in GSK2801's efficacy.
Conclusions:
- Inhibition of BAZ2A, BAZ2B, and BRD9 proteins with GSK2801 can overcome paclitaxel resistance in anaplastic thyroid cancer.
- MYCN is a significant downstream mediator of GSK2801's therapeutic effects.
- Targeting bromodomain proteins and MYCN concurrently with taxanes represents a promising therapeutic avenue for managing taxane-resistant ATC.
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