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ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer

Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the dept...

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Autores principales: Schultz, Christopher W, Zhang, Yang, Elmeskini, Rajaa, Zimmermann, Astrid, Fu, Haiqing, Murai, Yasuhisa, Wangsa, Darawalee, Kumar, Suresh, Takahashi, Nobuyuki, Atkinson, Devon, Saha, Liton Kumar, Lee, Chien‐Fei, Elenbaas, Brian, Desai, Parth, Sebastian, Robin, Sharma, Ajit Kumar, Abel, Melissa, Schroeder, Brett, Krishnamurthy, Manan, Kumar, Rajesh, Roper, Nitin, Aladjem, Mirit, Zenke, Frank T, Ohler, Zoe Weaver, Pommier, Yves, Thomas, Anish
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405061/
https://www.ncbi.nlm.nih.gov/pubmed/37491889
http://dx.doi.org/10.15252/emmm.202217313
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author Schultz, Christopher W
Zhang, Yang
Elmeskini, Rajaa
Zimmermann, Astrid
Fu, Haiqing
Murai, Yasuhisa
Wangsa, Darawalee
Kumar, Suresh
Takahashi, Nobuyuki
Atkinson, Devon
Saha, Liton Kumar
Lee, Chien‐Fei
Elenbaas, Brian
Desai, Parth
Sebastian, Robin
Sharma, Ajit Kumar
Abel, Melissa
Schroeder, Brett
Krishnamurthy, Manan
Kumar, Rajesh
Roper, Nitin
Aladjem, Mirit
Zenke, Frank T
Ohler, Zoe Weaver
Pommier, Yves
Thomas, Anish
author_facet Schultz, Christopher W
Zhang, Yang
Elmeskini, Rajaa
Zimmermann, Astrid
Fu, Haiqing
Murai, Yasuhisa
Wangsa, Darawalee
Kumar, Suresh
Takahashi, Nobuyuki
Atkinson, Devon
Saha, Liton Kumar
Lee, Chien‐Fei
Elenbaas, Brian
Desai, Parth
Sebastian, Robin
Sharma, Ajit Kumar
Abel, Melissa
Schroeder, Brett
Krishnamurthy, Manan
Kumar, Rajesh
Roper, Nitin
Aladjem, Mirit
Zenke, Frank T
Ohler, Zoe Weaver
Pommier, Yves
Thomas, Anish
author_sort Schultz, Christopher W
collection PubMed
description Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high‐throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First‐in‐class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S‐phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC‐driven non‐neuroendocrine tumors which are resistant to first‐line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.
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spelling pubmed-104050612023-08-08 ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer Schultz, Christopher W Zhang, Yang Elmeskini, Rajaa Zimmermann, Astrid Fu, Haiqing Murai, Yasuhisa Wangsa, Darawalee Kumar, Suresh Takahashi, Nobuyuki Atkinson, Devon Saha, Liton Kumar Lee, Chien‐Fei Elenbaas, Brian Desai, Parth Sebastian, Robin Sharma, Ajit Kumar Abel, Melissa Schroeder, Brett Krishnamurthy, Manan Kumar, Rajesh Roper, Nitin Aladjem, Mirit Zenke, Frank T Ohler, Zoe Weaver Pommier, Yves Thomas, Anish EMBO Mol Med Articles Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high‐throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First‐in‐class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S‐phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC‐driven non‐neuroendocrine tumors which are resistant to first‐line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174. John Wiley and Sons Inc. 2023-07-25 /pmc/articles/PMC10405061/ /pubmed/37491889 http://dx.doi.org/10.15252/emmm.202217313 Text en © 2023 The Authors. Published under the terms of the CC BY 4.0 license. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Schultz, Christopher W
Zhang, Yang
Elmeskini, Rajaa
Zimmermann, Astrid
Fu, Haiqing
Murai, Yasuhisa
Wangsa, Darawalee
Kumar, Suresh
Takahashi, Nobuyuki
Atkinson, Devon
Saha, Liton Kumar
Lee, Chien‐Fei
Elenbaas, Brian
Desai, Parth
Sebastian, Robin
Sharma, Ajit Kumar
Abel, Melissa
Schroeder, Brett
Krishnamurthy, Manan
Kumar, Rajesh
Roper, Nitin
Aladjem, Mirit
Zenke, Frank T
Ohler, Zoe Weaver
Pommier, Yves
Thomas, Anish
ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer
title ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer
title_full ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer
title_fullStr ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer
title_full_unstemmed ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer
title_short ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer
title_sort atr inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405061/
https://www.ncbi.nlm.nih.gov/pubmed/37491889
http://dx.doi.org/10.15252/emmm.202217313
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