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Unique features of trabectedin mechanism of action

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Abstract

Trabectedin (Yondelis®, ET-743) is a marine-derived natural product that was initially isolated from the marine ascidian Ecteinascidia turbinata and is currently prepared synthetically. Trabectedin is used as a single agent for the treatment of patients with soft tissue sarcoma after failure of doxorubicin or ifosfamide or who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin presents a complex mechanism of action affecting key cell biology processes in tumor cells as well as in the tumor microenvironment. The inhibition of trans-activated transcription and the interaction with DNA repair proteins appear as a hallmark of the antiproliferative activity of trabectedin. Inhibition of active transcription is achieved by an initial direct mechanism that involves interaction with RNA polymerase II, thereby inducing its ubiquitination and degradation by the proteasome. This subsequently modulates the production of cytokines and chemokines by tumor and tumor-associated macrophages. Another interesting effect on activated transcription is mediated by the displacement of oncogenic transcription factors from their target promoters, thereby affecting oncogenic signaling addiction. In addition, it is well established that DNA repair systems including transcription-coupled nucleotide excision repair and homologous recombination play a role in the antitumor activity of trabectedin. Ongoing studies are currently addressing how to exploit these unique mechanistic features of trabectedin to combine this agent either with immunological or microenvironmental modulators or with classical chemotherapeutic agents in a more rational manner.

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References

  1. Cuevas C, Francesch A (2009) Development of Yondelis (trabectedin, ET-743). A semisynthetic process solves the supply problem. Nat Prod Rep 26:322–337

    Article  CAS  PubMed  Google Scholar 

  2. Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW (1996) DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 35:13303–13309

    Article  CAS  PubMed  Google Scholar 

  3. Rinehart KLHTG, Fregeau NL, Stroh JG, Keifer A, Sun F, Li L-H, Martin G (1990) Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent antitumour agents from the Caribbean tunicate Ecteinascidia turbinata. J Org Chem 55:4512–4515

    Article  CAS  Google Scholar 

  4. Valoti G, Nicoletti MI, Pellegrino A, Jimeno J, Hendriks H, D’Incalci M, Faircloth G, Giavazzi R (1998) Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts. Clin Cancer Res 4:1977–1983

    CAS  PubMed  Google Scholar 

  5. Izbicka E, Lawrence R, Raymond E, Eckhardt G, Faircloth G, Jimeno J, Clark G, Von Hoff DD (1998) In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann Oncol 9:981–987

    Article  CAS  PubMed  Google Scholar 

  6. Delaloge S, Yovine A, Taamma A, Riofrio M, Brain E, Raymond E, Cottu P, Goldwasser F, Jimeno J, Misset JL, Marty M, Cvitkovic E (2001) Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients–preliminary evidence of activity. J Clin Oncol 19:1248–1255

    CAS  PubMed  Google Scholar 

  7. Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, Keohan ML, Samuels BL, Schuetze S, Lebedinsky C, Elsayed YA, Izquierdo MA, Gomez J, Park YC, Le Cesne A (2009) 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. J Clin Oncol 27:4188–4196

    Article  CAS  PubMed  Google Scholar 

  8. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR (2015) Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. doi:10.1200/JCO.2015.62.4734

    Google Scholar 

  9. Sessa C, De Braud F, Perotti A, Bauer J, Curigliano G, Noberasco C, Zanaboni F, Gianni L, Marsoni S, Jimeno J, D’Incalci M, Dall’o E, Colombo N (2005) Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails. J Clin Oncol 23:1867–1874

    Article  CAS  PubMed  Google Scholar 

  10. Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, Pujade-Lauraine E, Lisyanskaya AS, Makhson AN, Rolski J, Gorbounova VA, Ghatage P, Bidzinski M, Shen K, Ngan HY, Vergote IB, Nam JH, Park YC, Lebedinsky CA, Poveda AM (2010) Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer. J Clin Oncol 28:3107–3114

    Article  CAS  PubMed  Google Scholar 

  11. D’Incalci M, Galmarini CM (2010) A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther 9:2157–2163

    Article  PubMed  Google Scholar 

  12. Poindessous V, Koeppel F, Raymond E, Comisso M, Waters SJ, Larsen AK (2003) Marked activity of irofulven toward human carcinoma cells: comparison with cisplatin and ecteinascidin. Clin Cancer Res 9:2817–2825

    CAS  PubMed  Google Scholar 

  13. Friedman D, Hu Z, Kolb EA, Gorfajn B, Scotto KW (2002) Ecteinascidin-743 inhibits activated but not constitutive transcription. Cancer Res 62:3377–3381

    CAS  PubMed  Google Scholar 

  14. Minuzzo M, Marchini S, Broggini M, Faircloth G, D’Incalci M, Mantovani R (2000) Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci USA 97:6780–6784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Damia G, Silvestri S, Carrassa L, Filiberti L, Faircloth GT, Liberi G, Foiani M, D’Incalci M (2001) Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer 92:583–588

    Article  CAS  PubMed  Google Scholar 

  16. Herrero AB, Martin-Castellanos C, Marco E, Gago F, Moreno S (2006) Cross-talk between nucleotide excision and homologous recombination DNA repair pathways in the mechanism of action of antitumor trabectedin. Cancer Res 66:8155–8162

    Article  CAS  PubMed  Google Scholar 

  17. Takebayashi Y, Pourquier P, Zimonjic DB, Nakayama K, Emmert S, Ueda T, Urasaki Y, Kanzaki A, Akiyama SI, Popescu N, Kraemer KH, Pommier Y (2001) Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 7:961–966

    Article  CAS  PubMed  Google Scholar 

  18. Guirouilh-Barbat J, Sedelnikova OA, Bonner WM, Pommier Y (2006) Ecteinascidin-induced DNA double strand breaks. A link between histone gamma-H2AX, transcription-coupled nucleotide excision repair and Mre11 endonuclease. 97th AACR Annual Meeting Abstract nr 4642

  19. Soares DG, Escargueil AE, Poindessous V, Sarasin A, de Gramont A, Bonatto D, Henriques JA, Larsen AK (2007) Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743. Proc Natl Acad Sci USA 104:13062–13067

    Article  PubMed  PubMed Central  Google Scholar 

  20. Marco E, David-Cordonnier MH, Bailly C, Cuevas C, Gago F (2006) Further insight into the DNA recognition mechanism of trabectedin from the differential affinity of its demethylated analogue ecteinascidin ET729 for the triplet DNA binding site CGA. J Med Chem 49:6925–6929

    Article  CAS  PubMed  Google Scholar 

  21. Galmarini CM, D’Incalci M, Allavena P (2014) Trabectedin and plitidepsin: drugs from the sea that strike the tumor microenvironment. Mar Drugs 12:719–733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Scotto KW (2002) ET-743: more than an innovative mechanism of action. Anticancer Drugs 13(Suppl 1):S3–S6

    CAS  PubMed  Google Scholar 

  23. Jin S, Gorfajn B, Faircloth G, Scotto KW (2000) Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc Natl Acad Sci USA 97:6775–6779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Minuzzo M, Ceribelli M, Pitarque-Marti M, Borrelli S, Erba E, DiSilvio A, D’Incalci M, Mantovani R (2005) Selective effects of the anticancer drug Yondelis (ET-743) on cell-cycle promoters. Mol Pharmacol 68:1496–1503

    Article  CAS  PubMed  Google Scholar 

  25. Aune GJ, Takagi K, Sordet O, Guirouilh-Barbat J, Antony S, Bohr VA, Pommier Y (2008) Von Hippel-Lindau-coupled and transcription-coupled nucleotide excision repair-dependent degradation of RNA polymerase II in response to trabectedin. Clin Cancer Res 14:6449–6455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Feuerhahn S, Giraudon C, Martinez-Diez M, Bueren-Calabuig JA, Galmarini CM, Gago F, Egly JM (2011) XPF-dependent DNA breaks and RNA polymerase II arrest induced by antitumor DNA interstrand crosslinking-mimetic alkaloids. Chem Biol 18:988–999

    Article  CAS  PubMed  Google Scholar 

  27. Svejstrup JQ (2007) Contending with transcriptional arrest during RNAPII transcript elongation. Trends Biochem Sci 32:165–171

    Article  CAS  PubMed  Google Scholar 

  28. Bonfanti M, La Valle E, Fernandez Sousa Faro JM, Faircloth G, Caretti G, Mantovani R, D’Incalci M (1999) Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA. Anticancer Drug Des 14:179–186

    CAS  PubMed  Google Scholar 

  29. Grosso F, Jones RL, Demetri GD, Judson IR, Blay JY, Le Cesne A, Sanfilippo R, Casieri P, Collini P, Dileo P, Spreafico C, Stacchiotti S, Tamborini E, Tercero JC, Jimeno J, D’Incalci M, Gronchi A, Fletcher JA, Pilotti S, Casali PG (2007) Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol 8:595–602

    Article  CAS  PubMed  Google Scholar 

  30. Sandberg AA (2004) Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma. Cancer Genet Cytogenet 155:1–24

    Article  CAS  PubMed  Google Scholar 

  31. Le Cesne A, Cresta S, Maki RG, Blay JY, Verweij J, Poveda A, Casali PG, Balana C, Schoffski P, Grosso F, Lardelli P, Nieto A, Alfaro V, Demetri GD (2012) A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas. Eur J Cancer 48:3036–3044

    Article  PubMed  Google Scholar 

  32. Charytonowicz E, Terry M, Coakley K, Telis L, Remotti F, Cordon-Cardo C, Taub RN, Matushansky I (2012) PPARgamma agonists enhance ET-743-induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma. J Clin Invest 122:886–898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gronchi A, Bui BN, Bonvalot S, Pilotti S, Ferrari S, Hohenberger P, Hohl RJ, Demetri GD, Le Cesne A, Lardelli P, Perez I, Nieto A, Tercero JC, Alfaro V, Tamborini E, Blay JY (2012) Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma. Ann Oncol 23:771–776

    Article  CAS  PubMed  Google Scholar 

  34. Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M, Erba E, Grosso F, Gronchi A, Aman P, Casali P, D’Incalci M, Pilotti S, Mantovani R (2009) Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol Cancer Ther 8:449–457

    Article  CAS  PubMed  Google Scholar 

  35. Frapolli R, Tamborini E, Virdis E, Bello E, Tarantino E, Marchini S, Grosso F, Sanfilippo R, Gronchi A, Tercero JC, Peloso G, Casali P, Pilotti S, D’Incalci M (2010) Novel models of myxoid liposarcoma xenografts mimicking the biological and pharmacologic features of human tumors. Clin Cancer Res 16:4958–4967

    Article  CAS  PubMed  Google Scholar 

  36. Di Giandomenico S, Frapolli R, Bello E, Uboldi S, Licandro SA, Marchini S, Beltrame L, Brich S, Mauro V, Tamborini E, Pilotti S, Casali PG, Grosso F, Sanfilippo R, Gronchi A, Mantovani R, Gatta R, Galmarini CM, Sousa-Faro JM, D’Incalci M (2014) Mode of action of trabectedin in myxoid liposarcomas. Oncogene 33:5201–5210

    Article  PubMed  Google Scholar 

  37. Hancock JD, Lessnick SL (2008) A transcriptional profiling meta-analysis reveals a core EWS-FLI gene expression signature. Cell Cycle 7:250–256

    Article  CAS  PubMed  Google Scholar 

  38. Grohar PJ, Griffin LB, Yeung C, Chen QR, Pommier Y, Khanna C, Khan J, Helman LJ (2011) Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. Neoplasia 13:145–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zewail-Foote M, Hurley LH (1999) Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J Med Chem 42:2493–2497

    Article  CAS  PubMed  Google Scholar 

  40. De Silva IU, McHugh PJ, Clingen PH, Hartley JA (2000) Defining the roles of nucleotide excision repair and recombination in the repair of DNA interstrand cross-links in mammalian cells. Mol Cell Biol 20:7980–7990

    Article  PubMed  PubMed Central  Google Scholar 

  41. Frit P, Kwon K, Coin F, Auriol J, Dubaele S, Salles B, Egly JM (2002) Transcriptional activators stimulate DNA repair. Mol Cell 10:1391–1401

    Article  CAS  PubMed  Google Scholar 

  42. Schinecker TM, Perlow RA, Broyde S, Geacintov NE, Scicchitano DA (2003) Human RNA polymerase II is partially blocked by DNA adducts derived from tumorigenic benzo[c]phenanthrene diol epoxides: relating biological consequences to conformational preferences. Nucleic Acids Res 31:6004–6015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bueren-Calabuig JA, Giraudon C, Galmarini CM, Egly JM, Gago F (2011) Temperature-induced melting of double-stranded DNA in the absence and presence of covalently bonded antitumour drugs: insight from molecular dynamics simulations. Nucleic Acids Res 39:8248–8257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Erba E, Bergamaschi D, Bassano L, Damia G, Ronzoni S, Faircloth GT, D’Incalci M (2001) Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer 37:97–105

    Article  CAS  PubMed  Google Scholar 

  45. Colmegna B, Uboldi S, Erba E, D’Incalci M (2014) Resistance to minor groove binders. Drug Discov Today Technol 11:73–79

    Article  PubMed  Google Scholar 

  46. Soares DG, Machado MS, Rocca CJ, Poindessous V, Ouaret D, Sarasin A, Galmarini CM, Henriques JA, Escargueil AE, Larsen AK (2011) Trabectedin and its C subunit modified analogue PM01183 attenuate nucleotide excision repair and show activity toward platinum-resistant cells. Mol Cancer Ther 10:1481–1489

    Article  CAS  PubMed  Google Scholar 

  47. Arora S, Kothandapani A, Tillison K, Kalman-Maltese V, Patrick SM (2010) Downregulation of XPF-ERCC1 enhances cisplatin efficacy in cancer cells. DNA Repair (Amst) 9:745–753

    Article  CAS  Google Scholar 

  48. Handra-Luca A, Hernandez J, Mountzios G, Taranchon E, Lacau-St-Guily J, Soria JC, Fouret P (2007) Excision repair cross complementation group 1 immunohistochemical expression predicts objective response and cancer-specific survival in patients treated by Cisplatin-based induction chemotherapy for locally advanced head and neck squamous cell carcinoma. Clin Cancer Res 13:3855–3859

    Article  CAS  PubMed  Google Scholar 

  49. Soares DG, Larsen AK, Escargueil AE (2012) The DNA damage response to monofunctional anticancer DNA binders. Drug Discov Today Dis Models 9:e59–e67

    Article  CAS  Google Scholar 

  50. Tavecchio M, Natoli C, Ubezio P, Erba E, D’Incalci M (2007) Dynamics of cell cycle phase perturbations by trabectedin (ET-743) in nucleotide excision repair (NER)-deficient and NER-proficient cells, unravelled by a novel mathematical simulation approach. Cell Prolif 40:885–904

    Article  CAS  PubMed  Google Scholar 

  51. Tavecchio M, Simone M, Erba E, Chiolo I, Liberi G, Foiani M, D’Incalci M, Damia G (2008) Role of homologous recombination in trabectedin-induced DNA damage. Eur J Cancer 44:609–618

    Article  CAS  PubMed  Google Scholar 

  52. Monk BJ, Ghatage P, Parekh T, Henitz E, Knoblauch R, Matos-Pita AS, Nieto A, Park YC, Cheng PS, Li W, Favis R, Ricci D, Poveda A (2015) Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer—exploratory analysis of the phase 3 OVA-301 study. Ann Oncol 26(5):914–920. doi:10.1093/annonc/mdv071

    Article  CAS  PubMed  Google Scholar 

  53. Schoffski P, Taron M, Jimeno J, Grosso F, Sanfilipio R, Casali PG, Le Cesne A, Jones RL, Blay JY, Poveda A, Maki RG, Nieto A, Tercero JC, Rosell R (2011) Predictive impact of DNA repair functionality on clinical outcome of advanced sarcoma patients treated with trabectedin: a retrospective multicentric study. Eur J Cancer 47:1006–1012

    Article  CAS  PubMed  Google Scholar 

  54. Delaloge S, Wolp-Diniz R, Byrski T, Blum JL, Goncalves A, Campone M, Lardelli P, Kahatt C, Nieto A, Cullell-Young M, Lubinski J (2014) Activity of trabectedin in germline BRCA1/2-mutated metastatic breast cancer: results of an international first-in-class phase II study. Ann Oncol 25:1152–1158

    Article  CAS  PubMed  Google Scholar 

  55. Guirouilh-Barbat J, Redon C, Pommier Y (2008) Transcription-coupled DNA double-strand breaks are mediated via the nucleotide excision repair and the Mre11-Rad50-Nbs1 complex. Mol Biol Cell 19:3969–3981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Monk BJ, Kaye SB, Poveda A, Herzog TJ, Aracil M, Nieto A, Badri N, Parekh TV, Tanovic A, Galmarini CM (2014) Nibrin is a marker of clinical outcome in patients with advanced serous ovarian cancer treated in the phase III OVA-301 trial. Gynecol Oncol 132:176–180

    Article  CAS  PubMed  Google Scholar 

  57. Casado JA, Rio P, Marco E, Garcia-Hernandez V, Domingo A, Perez L, Tercero JC, Vaquero JJ, Albella B, Gago F, Bueren JA (2008) Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin. Mol Cancer Ther 7:1309–1318

    Article  CAS  PubMed  Google Scholar 

  58. Martinez S, Perez L, Galmarini CM, Aracil M, Tercero JC, Gago F, Albella B, Bueren JA (2013) Inhibitory effects of marine-derived DNA-binding anti-tumour tetrahydroisoquinolines on the Fanconi anaemia pathway. Br J Pharmacol 170:871–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. McHugh PJ, Spanswick VJ, Hartley JA (2001) Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance. Lancet Oncol 2:483–490

    Article  CAS  PubMed  Google Scholar 

  60. Soares DG, Poletto NP, Bonatto D, Salvador M, Schwartsmann G, Henriques JA (2005) Low cytotoxicity of ecteinascidin 743 in yeast lacking the major endonucleolytic enzymes of base and nucleotide excision repair pathways. Biochem Pharmacol 70:59–69

    Article  CAS  PubMed  Google Scholar 

  61. Allavena P, Signorelli M, Chieppa M, Erba E, Bianchi G, Marchesi F, Olimpio CO, Bonardi C, Garbi A, Lissoni A, de Braud F, Jimeno J, D’Incalci M (2005) Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res 65:2964–2971

    Article  CAS  PubMed  Google Scholar 

  62. Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, Erba E, Uboldi S, Zucchetti M, Pasqualini F, Nebuloni M, van Rooijen N, Mortarini R, Beltrame L, Marchini S, Fuso Nerini I, Sanfilippo R, Casali PG, Pilotti S, Galmarini CM, Anichini A, Mantovani A, D’Incalci M, Allavena P (2013) Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23:249–262

    Article  CAS  PubMed  Google Scholar 

  63. Germano G, Frapolli R, Simone M, Tavecchio M, Erba E, Pesce S, Pasqualini F, Grosso F, Sanfilippo R, Casali PG, Gronchi A, Virdis E, Tarantino E, Pilotti S, Greco A, Nebuloni M, Galmarini CM, Tercero JC, Mantovani A, D’Incalci M, Allavena P (2010) Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 70:2235–2244

    Article  CAS  PubMed  Google Scholar 

  64. Grohar PJ, Segars LE, Yeung C, Pommier Y, D’Incalci M, Mendoza A, Helman LJ (2014) Dual targeting of EWS-FLI1 activity and the associated DNA damage response with trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth. Clin Cancer Res 20:1190–1203

    Article  CAS  PubMed  Google Scholar 

  65. Lebel M, Leder P (1998) A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc Natl Acad Sci USA 95:13097–13102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pichierri P, Franchitto A, Mosesso P, Palitti F (2000) Werner’s syndrome cell lines are hypersensitive to camptothecin-induced chromosomal damage. Mutat Res 456:45–57

    Article  CAS  PubMed  Google Scholar 

  67. Boro A, Pretre K, Rechfeld F, Thalhammer V, Oesch S, Wachtel M, Schafer BW, Niggli FK (2012) Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing’s sarcoma. Int J Cancer 131:2153–2164

    Article  CAS  PubMed  Google Scholar 

  68. Burdach S (2014) Molecular precision chemotherapy: overcoming resistance to targeted therapies? Clin Cancer Res 20:1064–1066

    Article  CAS  PubMed  Google Scholar 

  69. D’Incalci M, Colombo T, Ubezio P, Nicoletti I, Giavazzi R, Erba E, Ferrarese L, Meco D, Riccardi R, Sessa C, Cavallini E, Jimeno J, Faircloth GT (2003) The combination of yondelis and cisplatin is synergistic against human tumor xenografts. Eur J Cancer 39:1920–1926

    Article  PubMed  Google Scholar 

  70. Sessa C, Cresta S, Noberasco C, Capri G, Gallerani E, De Braud F, Zucchetti M, D’Incalci M, Locatelli A, Marsoni S, Corradino I, Minoia C, Zintl P, Gianni L (2009) Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours. Eur J Cancer 45:2116–2122

    Article  CAS  PubMed  Google Scholar 

  71. Avila S, Martínez M, Moneo V, Martínez-Leal JF, Cuevas C, Garcia-Fernández LF, Galmarini CM (2014) Synergistic combination of Trabectedin and Olaparib in breast cancer tumor cell lines. 105th annual meeting of the American Association for Cancer Research 74: A1686

  72. Ordonez JL, Amaral AT, Carcaboso AM, Herrero-Martin D, del Carmen Garcia-Macias M, Sevillano V, Alonso D, Pascual-Pasto G, San-Segundo L, Vila-Ubach M, Rodrigues T, Fraile S, Teodosio C, Mayo-Iscar A, Aracil M, Galmarini CM, Tirado OM, Mora J, de Alava E (2015) The PARP inhibitor olaparib enhances the sensitivity of ewing sarcoma to trabectedin. Oncotarget 6(22):18875–18890

    Article  PubMed  PubMed Central  Google Scholar 

  73. Kachnic LA, Li L, Fournier L, Ferraiolo N, Dahm-Daphi J, Borgmann K, Willers H (2011) FANCD2 but not FANCA promotes cellular resistance to type II topoisomerase poisons. Cancer Lett 305:86–93

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, Sorbonne Universités et Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 938, Hôpital Sant-Antoine, 184 Rue du Faubourg Saint Antoine, 75571, Paris Cédex 12, France

    Annette K. Larsen

  2. Cell Biology Department, PharmaMar, Poligono Industrial La Mina, Avda. de los Reyes, 1, 28770, Colmenar Viejo, Madrid, Spain

    Carlos M. Galmarini

  3. Department of Oncology, IRCCS - Istiuto di Ricerche Farmacologiche “Mario Negri”, Via La Masa, 19, 20156, Milan, Italy

    Maurizio D’Incalci

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  1. Annette K. Larsen
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Correspondence to Carlos M. Galmarini.

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Larsen, A.K., Galmarini, C.M. & D’Incalci, M. Unique features of trabectedin mechanism of action. Cancer Chemother Pharmacol 77, 663–671 (2016). https://doi.org/10.1007/s00280-015-2918-1

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