Inhibition of the Met Receptor in Mesothelioma
Friday, November 25th, 2005.
Clinical Cancer Research. Vol. 11, 8122-8130, November 15, 2005. [Link]
Toru Mukohara1,3,4, Gabriel Civiello1, Ian J. Davis2,5, Michele L. Taffaro1, James Christensen6, David E. Fisher2,5, Bruce E. Johnson1,3,4 and Pasi A. Jänne1,3,4
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
Abstract
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.
Glossary
- oncology
- (on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.
- cell
- the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.
- cancer
- malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.
- mesothelioma
- a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.
