Molecular pharmacodynamics of PM02734 (elisidepsin) as single agent and in combination with erlotinib; synergistic activity in human non-small cell lung cancer cell lines and xenograft models

Yi He Ling, Miguel Aracil, José Jimeno, Roman Perez-Soler, Yiyu Zou

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37 Citations (Scopus)

Abstract

PM02734 (elisidepsin) is a novel marine-derived cyclic peptide belonging to the Kahalalide family of compounds currently under phase I development with early evidence of a positive therapeutic index. The cytotoxicity of PM02734 has been determined in a panel of human NSCLC (non-small cell lung cancer) cell lines. Western blot analysis showed a direct correlation between ErbB3 expression and cell sensitivity to PM02734. Furthermore, PM02734 was more effective in the induction of ErbB3 degradation and dephosphorylation than in that of ErbB2 and ErbB1 in human NSCLC cell lines. The combination of PM02734 and erlotinib was synergistic in all NSCLC cell lines tested, including erlotinib resistant cell lines, with combination indexes ranging between 0.59 and 0.81. The combination of PM02734 and erlotinib was more effective than either drug alone in mice inoculated intravenously (i.v.) with A549 cells. The combination of PM02734 and erlotinib was more effective in inhibiting AKT than either single agent alone in H322 cells. These results have provided a rational basis for an ongoing clinical trial to explore this combination in patients with advanced malignant solid tumours.

Original languageEnglish (US)
Pages (from-to)1855-1864
Number of pages10
JournalEuropean Journal of Cancer
Volume45
Issue number10
DOIs
StatePublished - Jul 2009

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Heterografts
Human Activities
Non-Small Cell Lung Carcinoma
Cell Line
Cyclic Peptides
Erlotinib Hydrochloride
elisidepsin
Western Blotting
Clinical Trials
Pharmaceutical Preparations
Neoplasms

Keywords

  • Elisidepsin
  • ErbB3
  • Erlotinib
  • NSCLC
  • PM02734

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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title = "Molecular pharmacodynamics of PM02734 (elisidepsin) as single agent and in combination with erlotinib; synergistic activity in human non-small cell lung cancer cell lines and xenograft models",
abstract = "PM02734 (elisidepsin) is a novel marine-derived cyclic peptide belonging to the Kahalalide family of compounds currently under phase I development with early evidence of a positive therapeutic index. The cytotoxicity of PM02734 has been determined in a panel of human NSCLC (non-small cell lung cancer) cell lines. Western blot analysis showed a direct correlation between ErbB3 expression and cell sensitivity to PM02734. Furthermore, PM02734 was more effective in the induction of ErbB3 degradation and dephosphorylation than in that of ErbB2 and ErbB1 in human NSCLC cell lines. The combination of PM02734 and erlotinib was synergistic in all NSCLC cell lines tested, including erlotinib resistant cell lines, with combination indexes ranging between 0.59 and 0.81. The combination of PM02734 and erlotinib was more effective than either drug alone in mice inoculated intravenously (i.v.) with A549 cells. The combination of PM02734 and erlotinib was more effective in inhibiting AKT than either single agent alone in H322 cells. These results have provided a rational basis for an ongoing clinical trial to explore this combination in patients with advanced malignant solid tumours.",
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AU - Perez-Soler, Roman

AU - Zou, Yiyu

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