A DNA damage repair gene‐associated signature predicts responses of patients with advanced soft‐tissue sarcoma to treatment with trabectedin

Moura, David S.; Peña‐Chilet, María; Varela, Juan Antonio Cordero; Álvarez-Alegret, Ramiro; Agra-Pujol, Carolina; Izquierdo, Francisco Miguel; Ramos, Rafael; Ortega, Luís; Martín-Dávila, Francisco; Castilla-Ramirez, Carolina; Hernández-León, Carmen Nieves; Romagosa, Cleofé; Salgado, María Ángeles Vaz; Bagué, Sílvia; Mayodormo-Aranda, Empar; Vicioso, Luís; Barceló, José Emilio Hernández; Rubió‐Casadevall, Jordi; Juan, Ana De; Fiaño-Valverde, Maria Concepcion; Hindi, Nadia; López-Álvarez, María; Lacerenza, Serena; Dopazo, Joaquín; Gutiérrez, Antonio; Álvarez, Rosa; Valverde, Claudia; Martínez‐Trufero, Javier; Martin‐Broto, Javier

doi:10.1002/1878-0261.12996

Cited by 12 publications

(17 citation statements)

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“…The analysis of data in the literature and the importance of DNA repair mechanisms in tumor progression led us to the characterization of the NER pathway, the DNA repair pathway often implicated in chemoresistance processes [ 35 , 36 , 37 ], in a cohort of STS patients enrolled at the Orthopaedic Oncology Unit of Careggi University Hospital. It has been demonstrated that efficiency changes of DNA repair capacity of NER genes can be related to the presence of single nucleotide polymorphisms (SNPs) that result in altered mRNA expression or protein activity [ 14 ]. A deficiency in the ability to repair DNA damages could therefore alter the response to treatment with a significant positive association between the polymorphism ERCC2 gene, Lys751Gln, but also ERCC1 , Asn118Asn with the improved cisplatin response in osteosarcoma [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that deficiencies in DNA repair capacity could have a role in affecting the response to DNA damaging agents [ 11 , 12 , 13 ]. At least six major DNA repair pathways, as well as numerous sub-pathways, are involved in the repair of damage [ 11 , 14 ]. In particular, the nucleotide excision repair (NER) pathway ( Figure 1 ) repairs bulky lesions and has been associated with tumor progression and response to chemotherapy [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Excision repair cross-complementing (ERCC) group 1 ( ERCC1 /XPA), group 2 ( ERCC2 /XPD), group 4 ( ERCC4 /XPF) and group 5 ( ERCC5 /XPG) are members of the NER pathway. It has been demonstrated that a deficiency of DNA repair capacity of NER genes can be related to the presence of single nucleotide polymorphisms (SNPs) that result in altered mRNA expression or protein activity [ 14 ]. A deficiency in the ability to repair DNA damages could therefore alter the response to treatment with a significant positive association between polymorphism ERCC2 gene, Lys751Gln, but also ERCC1 , Asn118Asn with the improved cisplatin response in osteosarcoma [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Alteration of the Nucleotide Excision Repair (NER) Pathway in Soft Tissue Sarcoma

Pasqui

Boddi

Campanacci

et al. 2022

IJMS

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Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unluckily restricted to a small subgroup of patients. Much of the inter-individual variability in treatment efficacy is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. The nucleotide excision repair (NER) system is the main defense mechanism for repairing DNA damage caused by carcinogens and chemotherapy drugs. Single nucleotide polymorphisms (SNPs) of NER pathway key genes, altering mRNA expression or protein activity, can be significantly associated with response to chemotherapy, toxicities, tumor relapse or risk of developing cancer. In the present study, in a cohort of STS patients, we performed DNA extraction and genotyping by SNP assay, RNA extraction and quantitative real-time reverse transcription PCR (qPCR), a molecular dynamics simulation in order to characterize the NER pathway in STS. We observed a severe deregulation of the NER pathway and we describe for the first time the effect of SNP rs1047768 in the ERCC5 structure, suggesting a role in modulating single-stranded DNA (ssDNA) binding. Our results evidenced, for the first time, the correlation between a specific genotype profile of ERCC genes and proficiency of the NER pathway in STS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alteration of the Nucleotide Excision Repair (NER) Pathway in Soft Tissue Sarcoma

Pasqui

Boddi

Campanacci

et al. 2022

IJMS

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“…Preclinical and clinical data confirmed feasibility and suggested hints of activity in a fraction of the enrolled patients, emphasizing the need to improve patient selection through the identification of specific predictive factors ( 12 , 13 ). Both drugs under study – trabectedin and olaparib – had already been studied as single agents, looking for predictive factors among the tightly intertwined mechanisms ruled by DNA Damage Response and Repair (DDRR) genes ( 14 – 24 ). However, potential predictive factors of combined trabectedin+olaparib treatment response have not been investigated, so far.…”

Section: Introductionmentioning

confidence: 99%

“…Trabectedin creates DNA adducts by interfering with active transcription, wherein its activity is dependent on transcription-coupled nucleotide excision repair (TC-NER) ( 25 – 27 ). NER defects make tumor cells less sensitive to trabectedin damage and high expression levels of ERCC1 and XPG/ERCC5 (“signs” of a proficient NER machinery) have been described as predictive of better response to trabectedin treatment ( 14 – 16 , 18 ). Tumor cells bearing homologous repair deficiency (HRD) are more sensitive to trabectedin-induced cell death, as they cannot recruit the proper machinery to repair the double-strand breaks (DSBs) generated upon trabectedin treatment.…”

Section: Introductionmentioning

confidence: 99%

DNA damage response and repair genes in advanced bone and soft tissue sarcomas: An 8-gene signature as a candidate predictive biomarker of response to trabectedin and olaparib combination

et al. 2022

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BackgroundAdvanced and unresectable bone and soft tissue sarcomas (BSTS) still represent an unmet medical need. We demonstrated that the alkylating agent trabectedin and the PARP1-inhibitor olaparib display antitumor activity in BSTS preclinical models. Moreover, in a phase Ib clinical trial (NCT02398058), feasibility, tolerability and encouraging results have been observed and the treatment combination is currently under study in a phase II trial (NCT03838744).MethodsDifferential expression of genes involved in DNA Damage Response and Repair was evaluated by Nanostring® technology, extracting RNA from pre-treatment tumor samples of 16 responder (≥6-month progression free survival) and 16 non-responder patients. Data validation was performed by quantitative real-time PCR, RNA in situ hybridization, and immunohistochemistry. The correlation between the identified candidate genes and both progression-free survival and overall survival was investigated in the publicly available dataset “Sarcoma (TCGA, The Cancer Genome Atlas)”.ResultsDifferential RNA expression analysis revealed an 8-gene signature (CDKN2A, PIK3R1, SLFN11, ATM, APEX2, BLM, XRCC2, MAD2L2) defining patients with better outcome upon trabectedin+olaparib treatment. In responder vs. non-responder patients, a significant differential expression of these genes was further confirmed by RNA in situ hybridization and by qRT-PCR and immunohistochemistry in selected experiments. Correlation between survival outcomes and genetic alterations in the identified genes was shown in the TCGA sarcoma dataset.ConclusionsThis work identified an 8-gene expression signature to improve prediction of response to trabectedin+olaparib combination in BSTS. The predictive role of these potential biomarkers warrants further investigation.

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HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study

Moura,

Mondaza-Hernandez,

Sanchez-Bustos

et al. 2024

Cell. Mol. Life Sci.

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HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.

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A DNA damage repair gene‐associated signature predicts responses of patients with advanced soft‐tissue sarcoma to treatment with trabectedin

Cited by 12 publications

References 43 publications

Alteration of the Nucleotide Excision Repair (NER) Pathway in Soft Tissue Sarcoma

Alteration of the Nucleotide Excision Repair (NER) Pathway in Soft Tissue Sarcoma

DNA damage response and repair genes in advanced bone and soft tissue sarcomas: An 8-gene signature as a candidate predictive biomarker of response to trabectedin and olaparib combination

HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study

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