Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783506445203931136
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
work_keys_str_mv AT kathawalarishilj abcg2overexpressioncontributestopevonedistatresistance
AT espitiaclaudiam abcg2overexpressioncontributestopevonedistatresistance
AT jonestracem abcg2overexpressioncontributestopevonedistatresistance
AT islamshariful abcg2overexpressioncontributestopevonedistatresistance
AT guptapranav abcg2overexpressioncontributestopevonedistatresistance
AT zhangyunkai abcg2overexpressioncontributestopevonedistatresistance
AT chenzhesheng abcg2overexpressioncontributestopevonedistatresistance
AT carewjennifers abcg2overexpressioncontributestopevonedistatresistance
AT nawrockisteffant abcg2overexpressioncontributestopevonedistatresistance