Therapeutic Targeting of Multiple Signaling Pathways in Malignant Pleural Mesothelioma

Vol. 68, No. 4-6, 2005

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Laboratory Investigation

Therapeutic Targeting of Multiple Signaling Pathways in Malignant Pleural Mesothelioma
Toru Mukohara^a-c, Gabriel Civiello^a, Bruce E. Johnson^a-c, Pasi A. Jänne^a-c

^aLowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute; Departments of Medicine,
^bBrigham and Women's Hospital and
^cHarvard Medical School, Boston, Mass., USA

Address of Corresponding Author

Oncology 2005;68:500-510 (DOI: 10.1159/000086994)

Key Words

Malignant mesothelioma
Epidermal growth factor receptor
Signal transduction

Abstract

The majority of malignant pleural mesotheliomas (MPMs) aberrantly express the epidermal growth factor receptor (ErbB1). We examined the efficacy of GW572016 (lapatinib), a dual inhibitor of ErbB1/ErbB2 with a panel of 10 MPM cell lines. Two of the 10 MPM cell lines, H2373 and H2452, underwent G1/S cell cycle arrest and growth inhibition with an IC₅₀ of 1 µM and 0.8 µM, respectively. There was no relationship between the presence or the amount of ErbB1, phospho-ErbB1, phospho-ErbB2, ErbB3, ErbB4, phospho-Akt, and Akt or the ability of lapatinib to inhibit phospho-ErbB1 in these cell lines compared to those that did not respond to lapatinib. The sensitive cell lines had a time-dependent decrease in phospho-Akt and/or ERK1/2, and an increase in p27 and when treated with lapatinib. The combination of lapatinib with U0126, LY294002 or rapamycin caused greater growth inhibition than either drug alone in the sensitive cell lines while this did not occur in the resistant cell lines. Our findings suggest that ErbB1 alone is a therapeutic target for the minority of mesotheliomas and that combining ErbB1 inhibitors with signal transduction inhibitors in mesothelioma will enhance their effectiveness. Furthermore, combinations of growth factor and signal transduction inhibitors may be needed to inhibit the growth of the majority of MPM cell lines, and therefore patients with MPM.

Author Contacts

Pasi A. Jänne MD, PhD
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, D1234
44 Binney Street
Boston, MA 02115 (USA)
Tel. +1 617 632 6076, Fax +1 617 632 5786, E-Mail pjanne@partners.org

Article Information

Received: December 9, 2004
Accepted after revision: February 12, 2005
Published online: July 13, 2005
Number of Print Pages : 11
Number of Figures : 6, Number of Tables : 0, Number of References : 39

Medline Abstract (ID 16020981)

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