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Inhibition of the Met Receptor in Mesothelioma

Authors' Affiliations: ¹ Lowe Center for Thoracic Oncology, Department of Medical Oncology, and ² Department of Pediatric Oncology, Dana-Farber Cancer Institute; ³ Department of Medicine, Brigham and Women's Hospital; ⁴ Harvard Medical School; and ⁵ Department of Medicine, Children's Hospital, Boston, Massachusetts and ⁶ Pfizer Global Research and Development, Department of Research Pharmacology, La Jolla Labs, La Jolla, California

Requests for reprints: Pasi A. Jänne, Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, D1234, 44 Binney Street, Boston, MA 02115. Phone: 617-632-6076; Fax: 617-632-5786; E-mail: pjanne{at}partners.org.

Background: Expression of the Met receptor and its ligand, hepatocyte growth factor (HGF), has been observed in 74% to 100% and 40% to 85% of malignant pleural mesothelioma (MPM) specimens, respectively. HGF stimulation has been shown to enhance MPM cell proliferation, migration, cell scattering, and invasiveness.

Experimental Design: To investigate a potential therapeutic role for the Met receptor in MPM, we examined the effects of PHA-665752, a specific small-molecule inhibitor of the Met receptor tyrosine kinase, in a panel of 10 MPM cell lines.

Results: Two of the cell lines, H2461 and JMN-1B, exhibited autocrine HGF production as measured by ELISA (3.9 and 10.5 ng/mL, respectively, versus <0.05 ng/mL in other cell lines). Evaluation of PHA-665752 across the 10 MPM cell lines indicated that despite Met expression in all cell lines, only in cell lines that exhibited a Met/HGF autocrine loop, H2461 and JMN-1B, did PHA-665752 inhibit growth with an IC₅₀ of 1 and 2 µmol/L, respectively. No activating mutations in Met were detected in any of the cell lines. Consistent with observed growth inhibition, PHA-665752 caused cell cycle arrest at G₁-S boundary accompanied by a dose-dependent decrease in phosphorylation of Met, p70S6K, Akt, and extracellular signal-regulated kinase 1/2. Growth of H2461 cells was also inhibited by neutralizing antibodies to HGF and by RNA interference knockdown of the Met receptor, confirming that growth inhibition observed was through a Met-dependent mechanism. PHA-665752 also reduced MPM in vitro cell migration and invasion.

Conclusions: Taken together, these findings suggest that inhibition of the Met receptor may be an effective therapeutic strategy for patients with MPM and provides a mechanism, the presence of a HGF/Met autocrine loop, by which to select patients for PHA-665752 treatment.

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