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Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome

Poly (ADPribose) polymerase inhibitors (PARPis) are clinically approved drugs designed according to the concept of synthetic lethality (SL) interaction. It is crucial to expand the scale of patients who can benefit from PARPis, and overcome drug resistance associated with it. Genetic interactions (G...

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Autores principales: Dong, Qi, Liu, Mingyue, Chen, Bo, Zhao, Zhangxiang, Chen, Tingting, Wang, Chengyu, Zhuang, Shuping, Li, Yawei, Wang, Yuquan, Ai, Liqiang, Liu, Yaoyao, Liang, Haihai, Qi, Lishuang, Gu, Yunyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379270/
https://www.ncbi.nlm.nih.gov/pubmed/34471490
http://dx.doi.org/10.1016/j.csbj.2021.08.007
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author Dong, Qi
Liu, Mingyue
Chen, Bo
Zhao, Zhangxiang
Chen, Tingting
Wang, Chengyu
Zhuang, Shuping
Li, Yawei
Wang, Yuquan
Ai, Liqiang
Liu, Yaoyao
Liang, Haihai
Qi, Lishuang
Gu, Yunyan
author_facet Dong, Qi
Liu, Mingyue
Chen, Bo
Zhao, Zhangxiang
Chen, Tingting
Wang, Chengyu
Zhuang, Shuping
Li, Yawei
Wang, Yuquan
Ai, Liqiang
Liu, Yaoyao
Liang, Haihai
Qi, Lishuang
Gu, Yunyan
author_sort Dong, Qi
collection PubMed
description Poly (ADPribose) polymerase inhibitors (PARPis) are clinically approved drugs designed according to the concept of synthetic lethality (SL) interaction. It is crucial to expand the scale of patients who can benefit from PARPis, and overcome drug resistance associated with it. Genetic interactions (GIs) include SL and synthetic viability (SV) that participate in drug response in cancer cells. Based on the hypothesis that mutated genes with SL or SV interactions with PARP1/2/3 are potential sensitive or resistant PARPis biomarkers, respectively, we developed a novel computational method to identify them. We analyzed fitness variation of cell lines to identify PARP1/2/3-related GIs according to CRISPR/Cas9 and RNA interference functional screens. Potential resistant/sensitive mutated genes were identified using pharmacogenomic datasets. We identified 41 candidate resistant and 130 candidate sensitive PARPi-response related genes, and observed that EGFR with gain-of-function mutation induced PARPi resistance, and predicted a combination therapy with PARP inhibitor (veliparib) and EGFR inhibitor (erlotinib) for lung cancer. We also revealed that a resistant gene set (TNN, PLEC, and TRIP12) in lower grade glioma and a sensitive gene set (BRCA2, TOP3A, and ASCC3) in ovarian cancer, which were associated with prognosis. Thus, cancer genome-derived GIs provide new insights for identifying PARPi biomarkers and a new avenue for precision therapeutics.
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spelling pubmed-83792702021-08-31 Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome Dong, Qi Liu, Mingyue Chen, Bo Zhao, Zhangxiang Chen, Tingting Wang, Chengyu Zhuang, Shuping Li, Yawei Wang, Yuquan Ai, Liqiang Liu, Yaoyao Liang, Haihai Qi, Lishuang Gu, Yunyan Comput Struct Biotechnol J Research Article Poly (ADPribose) polymerase inhibitors (PARPis) are clinically approved drugs designed according to the concept of synthetic lethality (SL) interaction. It is crucial to expand the scale of patients who can benefit from PARPis, and overcome drug resistance associated with it. Genetic interactions (GIs) include SL and synthetic viability (SV) that participate in drug response in cancer cells. Based on the hypothesis that mutated genes with SL or SV interactions with PARP1/2/3 are potential sensitive or resistant PARPis biomarkers, respectively, we developed a novel computational method to identify them. We analyzed fitness variation of cell lines to identify PARP1/2/3-related GIs according to CRISPR/Cas9 and RNA interference functional screens. Potential resistant/sensitive mutated genes were identified using pharmacogenomic datasets. We identified 41 candidate resistant and 130 candidate sensitive PARPi-response related genes, and observed that EGFR with gain-of-function mutation induced PARPi resistance, and predicted a combination therapy with PARP inhibitor (veliparib) and EGFR inhibitor (erlotinib) for lung cancer. We also revealed that a resistant gene set (TNN, PLEC, and TRIP12) in lower grade glioma and a sensitive gene set (BRCA2, TOP3A, and ASCC3) in ovarian cancer, which were associated with prognosis. Thus, cancer genome-derived GIs provide new insights for identifying PARPi biomarkers and a new avenue for precision therapeutics. Research Network of Computational and Structural Biotechnology 2021-08-10 /pmc/articles/PMC8379270/ /pubmed/34471490 http://dx.doi.org/10.1016/j.csbj.2021.08.007 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Dong, Qi
Liu, Mingyue
Chen, Bo
Zhao, Zhangxiang
Chen, Tingting
Wang, Chengyu
Zhuang, Shuping
Li, Yawei
Wang, Yuquan
Ai, Liqiang
Liu, Yaoyao
Liang, Haihai
Qi, Lishuang
Gu, Yunyan
Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome
title Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome
title_full Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome
title_fullStr Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome
title_full_unstemmed Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome
title_short Revealing biomarkers associated with PARP inhibitors based on genetic interactions in cancer genome
title_sort revealing biomarkers associated with parp inhibitors based on genetic interactions in cancer genome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379270/
https://www.ncbi.nlm.nih.gov/pubmed/34471490
http://dx.doi.org/10.1016/j.csbj.2021.08.007
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