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.
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.
Division of Medical Oncology, Albert Einstein College of Medicine, Bronx, New York, USA.
Yi-He
YH
Ling
Miguel
M
Aracil
José
J
Jimeno
Roman
R
Perez-Soler
Yiyu
Y
Zou
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D018739:Oncogene Proteins v-erbB / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D047630:Depsipeptides; D018739:Oncogene Proteins v-erbB; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C522358:elisidepsin; D000069347:Erlotinib Hydrochloride