Cargando…
Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors
Mutations in the isocitrate dehydrogenase-1 and -2 (IDH1/2) genes were first identified in glioma and acute myeloid leukemia (AML), and subsequently found in multiple other tumor types. These neomorphic mutations convert the normal product of enzyme, α-ketoglutarate (αKG), to the oncometabolite 2-hy...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127964/ https://www.ncbi.nlm.nih.gov/pubmed/34027408 http://dx.doi.org/10.1093/narcan/zcab018 |
_version_ | 1783694033972887552 |
---|---|
author | Sule, Amrita Van Doorn, Jinny Sundaram, Ranjini K Ganesa, Sachita Vasquez, Juan C Bindra, Ranjit S |
author_facet | Sule, Amrita Van Doorn, Jinny Sundaram, Ranjini K Ganesa, Sachita Vasquez, Juan C Bindra, Ranjit S |
author_sort | Sule, Amrita |
collection | PubMed |
description | Mutations in the isocitrate dehydrogenase-1 and -2 (IDH1/2) genes were first identified in glioma and acute myeloid leukemia (AML), and subsequently found in multiple other tumor types. These neomorphic mutations convert the normal product of enzyme, α-ketoglutarate (αKG), to the oncometabolite 2-hydroxyglutarate (2HG). Our group recently demonstrated that 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state referred to as ‘BRCAness’, which confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we sought to elucidate sensitivity of IDH1/2-mutant cells to DNA damage response (DDR) inhibitors and, whether combination therapies could enhance described synthetic lethal interactions. Here, we report that ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitors are active against IDH1/2-mutant cells, and that this activity is further potentiated in combination with PARP inhibitors. We demonstrate this interaction across multiple cell line models with engineered and endogenous IDH1/2 mutations, with robust anti-tumor activity in vitro and in vivo. Mechanistically, we found ATR and PARP inhibitor treatment induces premature mitotic entry, which is significantly elevated in the setting of IDH1/2-mutations. These data highlight the potential efficacy of targeting HR defects in IDH1/2-mutant cancers and support the development of this combination in future clinical trials. |
format | Online Article Text |
id | pubmed-8127964 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-81279642021-05-20 Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors Sule, Amrita Van Doorn, Jinny Sundaram, Ranjini K Ganesa, Sachita Vasquez, Juan C Bindra, Ranjit S NAR Cancer Nucleic Acid-Based Cancer Therapeutics Mutations in the isocitrate dehydrogenase-1 and -2 (IDH1/2) genes were first identified in glioma and acute myeloid leukemia (AML), and subsequently found in multiple other tumor types. These neomorphic mutations convert the normal product of enzyme, α-ketoglutarate (αKG), to the oncometabolite 2-hydroxyglutarate (2HG). Our group recently demonstrated that 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state referred to as ‘BRCAness’, which confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we sought to elucidate sensitivity of IDH1/2-mutant cells to DNA damage response (DDR) inhibitors and, whether combination therapies could enhance described synthetic lethal interactions. Here, we report that ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitors are active against IDH1/2-mutant cells, and that this activity is further potentiated in combination with PARP inhibitors. We demonstrate this interaction across multiple cell line models with engineered and endogenous IDH1/2 mutations, with robust anti-tumor activity in vitro and in vivo. Mechanistically, we found ATR and PARP inhibitor treatment induces premature mitotic entry, which is significantly elevated in the setting of IDH1/2-mutations. These data highlight the potential efficacy of targeting HR defects in IDH1/2-mutant cancers and support the development of this combination in future clinical trials. Oxford University Press 2021-05-17 /pmc/articles/PMC8127964/ /pubmed/34027408 http://dx.doi.org/10.1093/narcan/zcab018 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Nucleic Acid-Based Cancer Therapeutics Sule, Amrita Van Doorn, Jinny Sundaram, Ranjini K Ganesa, Sachita Vasquez, Juan C Bindra, Ranjit S Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors |
title | Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors |
title_full | Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors |
title_fullStr | Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors |
title_full_unstemmed | Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors |
title_short | Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors |
title_sort | targeting idh1/2 mutant cancers with combinations of atr and parp inhibitors |
topic | Nucleic Acid-Based Cancer Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127964/ https://www.ncbi.nlm.nih.gov/pubmed/34027408 http://dx.doi.org/10.1093/narcan/zcab018 |
work_keys_str_mv | AT suleamrita targetingidh12mutantcancerswithcombinationsofatrandparpinhibitors AT vandoornjinny targetingidh12mutantcancerswithcombinationsofatrandparpinhibitors AT sundaramranjinik targetingidh12mutantcancerswithcombinationsofatrandparpinhibitors AT ganesasachita targetingidh12mutantcancerswithcombinationsofatrandparpinhibitors AT vasquezjuanc targetingidh12mutantcancerswithcombinationsofatrandparpinhibitors AT bindraranjits targetingidh12mutantcancerswithcombinationsofatrandparpinhibitors |