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Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma

Blocking cancer genomic instability may prevent tumor diversification and escape from therapies. We show that, after MAPK inhibitor (MAPKi) therapy in patients and mice bearing patient-derived xenografts (PDX), acquired resistant genomes of metastatic cutaneous melanoma specifically amplify resistan...

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Autores principales: Dharanipragada, Prashanthi, Zhang, Xiao, Liu, Sixue, Lomeli, Shirley H., Hong, Aayoung, Wang, Yan, Yang, Zhentao, Lo, Kara Z., Vega-Crespo, Agustin, Ribas, Antoni, Moschos, Stergios J., Moriceau, Gatien, Lo, Roger S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068459/
https://www.ncbi.nlm.nih.gov/pubmed/36700848
http://dx.doi.org/10.1158/2159-8290.CD-22-0787
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author Dharanipragada, Prashanthi
Zhang, Xiao
Liu, Sixue
Lomeli, Shirley H.
Hong, Aayoung
Wang, Yan
Yang, Zhentao
Lo, Kara Z.
Vega-Crespo, Agustin
Ribas, Antoni
Moschos, Stergios J.
Moriceau, Gatien
Lo, Roger S.
author_facet Dharanipragada, Prashanthi
Zhang, Xiao
Liu, Sixue
Lomeli, Shirley H.
Hong, Aayoung
Wang, Yan
Yang, Zhentao
Lo, Kara Z.
Vega-Crespo, Agustin
Ribas, Antoni
Moschos, Stergios J.
Moriceau, Gatien
Lo, Roger S.
author_sort Dharanipragada, Prashanthi
collection PubMed
description Blocking cancer genomic instability may prevent tumor diversification and escape from therapies. We show that, after MAPK inhibitor (MAPKi) therapy in patients and mice bearing patient-derived xenografts (PDX), acquired resistant genomes of metastatic cutaneous melanoma specifically amplify resistance-driver, nonhomologous end-joining (NHEJ), and homologous recombination repair (HRR) genes via complex genomic rearrangements (CGR) and extrachromosomal DNAs (ecDNA). Almost all sensitive and acquired-resistant genomes harbor pervasive chromothriptic regions with disproportionately high mutational burdens and significant overlaps with ecDNA and CGR spans. Recurrently, somatic mutations within ecDNA and CGR amplicons enrich for HRR signatures, particularly within acquired resistant tumors. Regardless of sensitivity or resistance, breakpoint–junctional sequence analysis suggests NHEJ as critical to double-stranded DNA break repair underlying CGR and ecDNA formation. In human melanoma cell lines and PDXs, NHEJ targeting by a DNA-PK(CS) inhibitor prevents/delays acquired MAPKi resistance by reducing the size of ecDNAs and CGRs early on combination treatment. Thus, targeting the causes of genomic instability prevents acquired resistance. SIGNIFICANCE: Acquired resistance often results in heterogeneous, redundant survival mechanisms, which challenge strategies aimed at reversing resistance. Acquired-resistant melanomas recurrently evolve resistance-driving and resistance-specific amplicons via ecDNAs and CGRs, thereby nominating chromothripsis–ecDNA–CGR biogenesis as a resistance-preventive target. Specifically, targeting DNA-PK(CS)/NHEJ prevents resistance by suppressing ecDNA/CGR rearrangements in MAPKi-treated melanomas. This article is highlighted in the In This Issue feature, p. 799
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spelling pubmed-100684592023-04-04 Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma Dharanipragada, Prashanthi Zhang, Xiao Liu, Sixue Lomeli, Shirley H. Hong, Aayoung Wang, Yan Yang, Zhentao Lo, Kara Z. Vega-Crespo, Agustin Ribas, Antoni Moschos, Stergios J. Moriceau, Gatien Lo, Roger S. Cancer Discov Research Articles Blocking cancer genomic instability may prevent tumor diversification and escape from therapies. We show that, after MAPK inhibitor (MAPKi) therapy in patients and mice bearing patient-derived xenografts (PDX), acquired resistant genomes of metastatic cutaneous melanoma specifically amplify resistance-driver, nonhomologous end-joining (NHEJ), and homologous recombination repair (HRR) genes via complex genomic rearrangements (CGR) and extrachromosomal DNAs (ecDNA). Almost all sensitive and acquired-resistant genomes harbor pervasive chromothriptic regions with disproportionately high mutational burdens and significant overlaps with ecDNA and CGR spans. Recurrently, somatic mutations within ecDNA and CGR amplicons enrich for HRR signatures, particularly within acquired resistant tumors. Regardless of sensitivity or resistance, breakpoint–junctional sequence analysis suggests NHEJ as critical to double-stranded DNA break repair underlying CGR and ecDNA formation. In human melanoma cell lines and PDXs, NHEJ targeting by a DNA-PK(CS) inhibitor prevents/delays acquired MAPKi resistance by reducing the size of ecDNAs and CGRs early on combination treatment. Thus, targeting the causes of genomic instability prevents acquired resistance. SIGNIFICANCE: Acquired resistance often results in heterogeneous, redundant survival mechanisms, which challenge strategies aimed at reversing resistance. Acquired-resistant melanomas recurrently evolve resistance-driving and resistance-specific amplicons via ecDNAs and CGRs, thereby nominating chromothripsis–ecDNA–CGR biogenesis as a resistance-preventive target. Specifically, targeting DNA-PK(CS)/NHEJ prevents resistance by suppressing ecDNA/CGR rearrangements in MAPKi-treated melanomas. This article is highlighted in the In This Issue feature, p. 799 American Association for Cancer Research 2023-04-03 2023-01-26 /pmc/articles/PMC10068459/ /pubmed/36700848 http://dx.doi.org/10.1158/2159-8290.CD-22-0787 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Research Articles
Dharanipragada, Prashanthi
Zhang, Xiao
Liu, Sixue
Lomeli, Shirley H.
Hong, Aayoung
Wang, Yan
Yang, Zhentao
Lo, Kara Z.
Vega-Crespo, Agustin
Ribas, Antoni
Moschos, Stergios J.
Moriceau, Gatien
Lo, Roger S.
Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma
title Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma
title_full Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma
title_fullStr Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma
title_full_unstemmed Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma
title_short Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma
title_sort blocking genomic instability prevents acquired resistance to mapk inhibitor therapy in melanoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068459/
https://www.ncbi.nlm.nih.gov/pubmed/36700848
http://dx.doi.org/10.1158/2159-8290.CD-22-0787
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