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ABCG2 Overexpression Contributes to Pevonedistat Resistance
MLN4924 (pevonedistat) is a first-in-class NEDD8-activating enzyme (NAE) inhibitor in clinical trials for the treatment of solid tumors and hematologic malignancies. Despite the promising activity of MLN4924 observed in early trials, drug resistance has been noted in some patients. Identifying the u...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072604/ https://www.ncbi.nlm.nih.gov/pubmed/32059437 http://dx.doi.org/10.3390/cancers12020429 |
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author | Kathawala, Rishil J. Espitia, Claudia M. Jones, Trace M. Islam, Shariful Gupta, Pranav Zhang, Yun-Kai Chen, Zhe-Sheng Carew, Jennifer S. Nawrocki, Steffan T. |
author_facet | Kathawala, Rishil J. Espitia, Claudia M. Jones, Trace M. Islam, Shariful Gupta, Pranav Zhang, Yun-Kai Chen, Zhe-Sheng Carew, Jennifer S. Nawrocki, Steffan T. |
author_sort | Kathawala, Rishil J. |
collection | PubMed |
description | MLN4924 (pevonedistat) is a first-in-class NEDD8-activating enzyme (NAE) inhibitor in clinical trials for the treatment of solid tumors and hematologic malignancies. Despite the promising activity of MLN4924 observed in early trials, drug resistance has been noted in some patients. Identifying the underlying cause of treatment failure may help to better stratify patients that are most likely to benefit from this novel agent. Early preclinical studies revealed that the development of NAEβ mutations promotes resistance to MLN4924. However, these mutations have not been detected in patients that are relapsed/refractory to MLN4924, suggesting that other mechanisms are driving clinical resistance. To better understand the potential mechanisms of MLN4924 resistance, we generated MLN4924-resistant ovarian cancer cells. Interestingly, these cells did not develop mutations in NAEβ. Transcriptome analyses revealed that one of the most upregulated genes in resistant cells was ABCG2. This result was validated by quantitative real-time PCR and immunoblotting. Importantly, the sensitivity of MLN4924-resistant cells was restored by lentiviral short hairpin RNA (shRNA) targeting ABCG2. Further investigation using ABCG2-overexpressing NCI-H460/MX20 cells determined that these cells are resistant to the anticancer effects of MLN4924 and can be sensitized by co-treatment with the ABCG2 inhibitors YHO-13351 and fumitremorgin C. Finally, HEK293 models with overexpression of wild-type ABCG2 (R482) and variants (R482G and R482T) all demonstrated significant resistance to MLN4924 compared to wild-type cells. Overall, these findings define an important molecular resistance mechanism to MLN4924 and demonstrate that ABCG2 may be a useful clinical biomarker that predicts resistance to MLN4924 treatment. |
format | Online Article Text |
id | pubmed-7072604 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70726042020-03-19 ABCG2 Overexpression Contributes to Pevonedistat Resistance Kathawala, Rishil J. Espitia, Claudia M. Jones, Trace M. Islam, Shariful Gupta, Pranav Zhang, Yun-Kai Chen, Zhe-Sheng Carew, Jennifer S. Nawrocki, Steffan T. Cancers (Basel) Article MLN4924 (pevonedistat) is a first-in-class NEDD8-activating enzyme (NAE) inhibitor in clinical trials for the treatment of solid tumors and hematologic malignancies. Despite the promising activity of MLN4924 observed in early trials, drug resistance has been noted in some patients. Identifying the underlying cause of treatment failure may help to better stratify patients that are most likely to benefit from this novel agent. Early preclinical studies revealed that the development of NAEβ mutations promotes resistance to MLN4924. However, these mutations have not been detected in patients that are relapsed/refractory to MLN4924, suggesting that other mechanisms are driving clinical resistance. To better understand the potential mechanisms of MLN4924 resistance, we generated MLN4924-resistant ovarian cancer cells. Interestingly, these cells did not develop mutations in NAEβ. Transcriptome analyses revealed that one of the most upregulated genes in resistant cells was ABCG2. This result was validated by quantitative real-time PCR and immunoblotting. Importantly, the sensitivity of MLN4924-resistant cells was restored by lentiviral short hairpin RNA (shRNA) targeting ABCG2. Further investigation using ABCG2-overexpressing NCI-H460/MX20 cells determined that these cells are resistant to the anticancer effects of MLN4924 and can be sensitized by co-treatment with the ABCG2 inhibitors YHO-13351 and fumitremorgin C. Finally, HEK293 models with overexpression of wild-type ABCG2 (R482) and variants (R482G and R482T) all demonstrated significant resistance to MLN4924 compared to wild-type cells. Overall, these findings define an important molecular resistance mechanism to MLN4924 and demonstrate that ABCG2 may be a useful clinical biomarker that predicts resistance to MLN4924 treatment. MDPI 2020-02-12 /pmc/articles/PMC7072604/ /pubmed/32059437 http://dx.doi.org/10.3390/cancers12020429 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kathawala, Rishil J. Espitia, Claudia M. Jones, Trace M. Islam, Shariful Gupta, Pranav Zhang, Yun-Kai Chen, Zhe-Sheng Carew, Jennifer S. Nawrocki, Steffan T. ABCG2 Overexpression Contributes to Pevonedistat Resistance |
title | ABCG2 Overexpression Contributes to Pevonedistat Resistance |
title_full | ABCG2 Overexpression Contributes to Pevonedistat Resistance |
title_fullStr | ABCG2 Overexpression Contributes to Pevonedistat Resistance |
title_full_unstemmed | ABCG2 Overexpression Contributes to Pevonedistat Resistance |
title_short | ABCG2 Overexpression Contributes to Pevonedistat Resistance |
title_sort | abcg2 overexpression contributes to pevonedistat resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072604/ https://www.ncbi.nlm.nih.gov/pubmed/32059437 http://dx.doi.org/10.3390/cancers12020429 |
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