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

Predictive biomarkers of trabectedin represent an unmet need in advanced soft‐tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR‐related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six‐gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high‐risk gene signature group showed a significantly worse progression‐free survival compared with patients in the low‐risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.

[1]  J. Martín-Broto,et al.  CUL4A, ERCC5, and ERCC1 as Predictive Factors for Trabectedin Efficacy in Advanced Soft Tissue Sarcomas (STS): A Spanish Group for Sarcoma Research (GEIS) Study , 2020, Cancers.

[2]  Robin L. Jones,et al.  Different approaches to advanced soft tissue sarcomas depending on treatment line, goal of therapy and histological subtype , 2020, Expert review of anticancer therapy.

[3]  J. Blay,et al.  Assessment of Safety and Efficacy of Combined Trabectedin and Low-Dose Radiotherapy for Patients With Metastatic Soft-Tissue Sarcomas: A Nonrandomized Phase 1/2 Clinical Trial. , 2020, JAMA oncology.

[4]  Dongyun He,et al.  Exonuclease 1 (Exo1) Participates in Mammalian Non-Homologous End Joining and Contributes to Drug Resistance in Ovarian Cancer , 2020, Medical science monitor : international medical journal of experimental and clinical research.

[5]  J. Blay,et al.  Trabectedin and RAdiotherapy in Soft Tissue Sarcoma (TRASTS): Results of a Phase I Study in Myxoid Liposarcoma from Spanish (GEIS), Italian (ISG), French (FSG) Sarcoma Groups , 2019, EClinicalMedicine.

[6]  S. Elledge,et al.  Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets. , 2019, Molecular cell.

[7]  C. Galmarini,et al.  The Antitumor Drugs Trabectedin and Lurbinectedin Induce Transcription-Dependent Replication Stress and Genome Instability , 2018, Molecular Cancer Research.

[8]  Y. D'Alessandra,et al.  Direct screening of plasma circulating microRNAs , 2018, RNA biology.

[9]  M. Zucchetti,et al.  Trabectedin and olaparib in patients with advanced and non-resectable bone and soft-tissue sarcomas (TOMAS): an open-label, phase 1b study from the Italian Sarcoma Group. , 2018, The Lancet. Oncology.

[10]  B. Kerns,et al.  Developmental profiling of microRNAs in the human embryonic inner ear , 2018, PloS one.

[11]  Md Akram Hossain,et al.  APE2 promotes DNA damage response pathway from a single-strand break , 2018, Nucleic acids research.

[12]  J. Cogswell,et al.  Evaluation and selection of a non-PCR based technology for improved gene expression profiling from clinical formalin-fixed, paraffin-embedded samples. , 2016, Bioanalysis.

[13]  S. Pignata,et al.  Prospective phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: the MITO 15 trial. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[14]  C. Galmarini,et al.  Unique features of trabectedin mechanism of action , 2016, Cancer Chemotherapy and Pharmacology.

[15]  F. Bertucci,et al.  BRCA1 haplotype and clinical benefit of trabectedin in soft-tissue sarcoma patients , 2015, British Journal of Cancer.

[16]  Kai Huang,et al.  Identification of Poly(ADP-Ribose) Polymerase-1 as a Cell Cycle Regulator through Modulating Sp1 Mediated Transcription in Human Hepatoma Cells , 2013, PloS one.

[17]  N. Penel,et al.  Efficacy and safety of pharmacological interventions in second- or later-line treatment of patients with advanced soft tissue sarcoma: a systematic review , 2013, BMC Cancer.

[18]  Antonio Nieto,et al.  Trabectedin in patients with advanced non-small-cell lung cancer (NSCLC) with XPG and/or ERCC1 overexpression and BRCA1 underexpression and pretreated with platinum. , 2012, Lung cancer.

[19]  J. Blay,et al.  ERCC5/XPG, ERCC1, and BRCA1 gene status and clinical benefit of trabectedin in patients with soft tissue sarcoma , 2011, Cancer.

[20]  J. Besalduch,et al.  Yondelis® (ET-743, Trabectedin) sensitizes cancer cell lines to CD95-mediated cell death: new molecular insight into the mechanism of action. , 2011, European journal of pharmacology.

[21]  J. Blay,et al.  Predictive impact of DNA repair functionality on clinical outcome of advanced sarcoma patients treated with trabectedin: a retrospective multicentric study. , 2011, European journal of cancer.

[22]  C. E. Schrader,et al.  Apurinic/Apyrimidinic Endonuclease 2 Is Necessary for Normal B Cell Development and Recovery of Lymphoid Progenitors after Chemotherapeutic Challenge , 2011, The Journal of Immunology.

[23]  V. Schreiber,et al.  Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression , 2011, Proceedings of the National Academy of Sciences.

[24]  Robin L. Jones,et al.  Clinical Benefit of Second-Line Palliative Chemotherapy in Advanced Soft-Tissue Sarcoma , 2010, Sarcoma.

[25]  P. Allavena,et al.  Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. , 2010, Cancer research.

[26]  M. Robinson,et al.  A scaling normalization method for differential expression analysis of RNA-seq data , 2010, Genome Biology.

[27]  J. Blay,et al.  Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  M. Rossi,et al.  Poly(ADP-ribosyl)ation is implicated in the G0–G1 transition of resting cells , 2008, Oncogene.

[29]  J. Blay,et al.  Phase I Combination Study of Trabectedin and Doxorubicin in Patients with Soft-Tissue Sarcoma , 2008, Clinical Cancer Research.

[30]  R. Sánchez-Prieto,et al.  In vitro radiosensitisation by trabectedin in human cancer cell lines. , 2008, European journal of cancer.

[31]  M. Robinson,et al.  Small-sample estimation of negative binomial dispersion, with applications to SAGE data. , 2007, Biostatistics.

[32]  G. Poirier,et al.  PARP‐3 associates with polycomb group bodies and with components of the DNA damage repair machinery , 2007, Journal of cellular biochemistry.

[33]  P. Allavena,et al.  Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. , 2005, Cancer research.

[34]  C. Simbulan-Rosenthal,et al.  PARP-1 binds E2F-1 independently of its DNA binding and catalytic domains, and acts as a novel coactivator of E2F-1-mediated transcription during re-entry of quiescent cells into S phase , 2003, Oncogene.

[35]  J. Vonesch,et al.  PARP-3 localizes preferentially to the daughter centriole and interferes with the G1/S cell cycle progression , 2003, Journal of Cell Science.

[36]  J. Pačes,et al.  Cloning and expression of PARP-3 (Adprt3) and U3-55k, two genes closely linked on mouse chromosome 9. , 2002, Folia biologica.

[37]  Y. Pommier,et al.  Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair , 2001, Nature Medicine.

[38]  M D'Incalci,et al.  Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. , 2001, European journal of cancer.

[39]  R. Mantovani,et al.  Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Johansson.  A human poly(ADP-ribose) polymerase gene family (ADPRTL): cDNA cloning of two novel poly(ADP-ribose) polymerase homologues. , 1999, Genomics.

[41]  E. Nigg,et al.  MAT1, cdk7 and cyclin H form a kinase complex which is UV light‐sensitive upon association with TFIIH. , 1996, The EMBO journal.

[42]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .