Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets

Abstract

c-Met and receptor originated from nantes (RON) are structurally related transmembrane phosphotyrosine kinase receptors. c-Met and RON show increased expression or activity in a variety of tumors leading to tumor progression and may play a role in acquired resistance to therapy. Although often co-expressed, the distinct functional roles of c-Met and RON are not fully understood. c-Met and RON form both activated homodimers and heterodimers with themselves and other families of phosphotyrosine kinase receptors. Inhibitors for c-Met and RON including small molecular weigh kinase inhibitors and neutralizing antibodies are in pre-clinical investigation and clinical trials. Several of the tyrosine kinase inhibitors have activity against both c-Met and RON kinases whereas the antibodies generally are target specific. As with many targeted agents used to treat solid tumors, it is likely that c-Met/RON inhibitors will have greater benefit when used in combination with chemotherapy or other targeted agents. A careful analysis of c-Met/RON expression or activity and a better elucidation of how they influence cell signaling will be useful in predicting which tumors respond best to these inhibitors as well as determining which agents can be used with these inhibitors for combined therapy.

Figure 1. An illustration representing the structural and cell signaling domains and approaches for targeting c-Met and RON kinases for therapy

Mature c-Met and RON are structurally similar and are composed of an extracellular α-chain and a β-chain The extracellular domains include the semaphorin (SEMA) that possess ligand binding function, plexin-semaphorin-integrin (PSI) and the immunoglobulin-like plexin transcription (ITP), a transmembrane (TM) and an intracellular tyrosine kinase (TK) domain. Ligand binding, HGF for c-Met and MSP for RON, results in dimerization and phosphorylation in the TK domain leading to conformational changes and autophosphorylation of the C-terminal end of the receptor. The C-terminal phosphorylation of the receptor recruits adaptor proteins generally Gab1 for RON and Grb2 for c-Met which in turn leads to activation of various signaling cascades including PI3K/AKT and Ras/MAPK. Current strategies for targeting c-Met and RON signaling include neutralizing antibodies to the receptors or their ligands and small molecular weight tyrosine kinase inhibitors.

Figure 2. An illustration representing interaction of c-Met or RON with other cell surface receptors

Homodimerization of c-Met or RON appears preferable although c-Met and RON can form heterodimers leading to transphosphorylation. c-Met and RON may interact with and transphosphorylate other receptor tyrosine kinases including members of the EGFR family. A separate type of interaction for c-Met is with CD44, a non-kinase transmembrane receptor. Isoforms of CD44 bind and apparently sequester HGF at the membrane, acting a co-receptor for presentation of ligand to c-Met.

Figure 3. Inhibiting c-Met expression or activity prevents growth of tumor spheres

Cells from CFPac-1 pancreatic cancer cell line were separated by flow cytometry on the basis of high CD44 expression. The high CD44 expressing cell population show high expression of c-Met and where able to grow after repeated passages as tumor spheres. (A) c-Met was knocked down using a shRNA approach in high CD44 expressing pancreatic cancer cells; (B) photo showing that CD44 high expressing cells were able to grow as tumor spheres in stem cell medium; (C) Knockdown of c-Met by shRNA inhibited the ability of high CD44 expressing pancreatic cancer cells to grow as tumor spheres and (D) treatment of high CD44 expressing cancer cells with a c-Met tyrosine kinase inhibitor prevented their growth as tumor spheres.