c-Met is rapidly emerging as an important target for cancer therapy. Overexpression of c-Met is associated with poor patient survival or metastasis in numerous human malignancies (Comoglio et al., 2008
). Cumulative in vitro
and in vivo
evidences demonstrates that c-Met targeting can effectively attenuate tumor growth, invasion and metastasis (Comoglio et al., 2008
), however, the mechanisms remain to be fully elucidated. Phase I and II human clinical trials of multiple c-Met targeting approaches are currently underway, including monoclonal antibodies against HGF (hepatocyte growth factor, the ligand of c-Met) and small molecule tyrosine kinase inhibitors (TKIs) against c-Met. Although the results of clinical trials are yet to be revealed, many of the c-Met TKIs demonstrated promising preclinical efficacy in inhibiting tumor growth, invasion, metastasis, as well as angiogenesis (Comoglio et al., 2008
) resulting in optimism for the approach.
Gain-of-function aberrations affecting c-Met, which causes inappropriate activation of c-Met, is an oncogenic event (Cooper et al., 1984
; Wang et al., 2001
). In various cancers, gain-of-function of c-Met occurs via genetic alterations (e.g. gene amplification or rearrangement, activating mutation), overexpression (by transcriptional upregulation), as well as upregulation of its ligand, HGF (Comoglio et al., 2008
; Nakamura et al., 2008
). Although the incidence of activating c-Met mutation or gene rearrangement is relatively low in human cancers, overexpression of c-Met protein (either via transcriptional activation or gene amplification) is observed in >50–80% of a wide variety of cancers (Comoglio et al., 2008
). Recently, Wang et al
showed that overexpression of wildtype c-Met in hepatocytes was sufficient to cause liver cancer (Wang et al., 2001
), providing support for c-Met overexpression being a causal event in cancer. Targeting of aberrant c-Met activation, either overexpression of wildtype or activating mutants of c-Met, has demonstrated therapeutic efficacy in diverse cancer models (Stabile et al., 2004
; Comoglio et al., 2008
In view of this, several novel and versatile c-Met inhibitors with potent inhibitory activities against both overexpressed wildtype as well as activating mutants of c-Met have been developed (Bellon et al., 2008
). AM7 is a recently developed c-Met inhibitor with a distinct binding mode to c-Met as compared to classical c-Met TKI “tool compound” (e.g. SU11274) (Bellon et al., 2008
). X-ray crystallography revealed that AM7 binds to the kinase linker region and extends into a hydrophobic binding site of c-Met, thus allowing interaction with and subsequent inhibition of both wildtype and mutated c-Met (Bellon et al., 2008
). Preclinical studies are underway to determine the therapeutic efficacy of this new class of c-Met TKI.
Nasopharyngeal cancer (NPC) is a highly metastatic head and neck cancer prevalent in Asia, with an annual incidence of 15-30/100,000cases/year (comparable to that of pancreatic cancer in the US)(Yu and Yuan, 2002
; Anderson et al., 2006
). Over 60–70% of NPC patients have advanced disease (Stage IIb or IV) at the time of diagnosis. c-Met overexpression correlates with poor survival and metastasis in NPC (Qian et al., 2002
), suggesting that c-Met may be an etiological agent and therapeutic target in this disease. In this study, we demonstrate that inhibition of c-Met (by AM7 and a c-Met TKI tool compound SU11274) blocks growth and invasion of NPC cells. Strikingly, c-Met inhibition decreased p53 and downregulated TIGAR, resulting in a significant reduction of cellular NADPH levels. As NADPH provides reducing power required for cell survival and proliferation, this may represent a novel mechanistic target of c-Met TKI. Indeed, overexpression of TIGAR rescued NPC cells from both AM7- and SU11274-mediated growth inhibition, demonstrating the mechanistic importance of TIGAR down-modulation. The effects of c-Met inhibition on TIGAR and NADPH levels were generalizable with both c-Met TKIs (AM7 and SU11274) demonstrating activity across multiple cell lines. Our findings not only demonstrated the therapeutic potential of c-Met targeting in NPC, but also revealed novel effects of c-Met targeting on NADPH regulation in cancer cells via TIGAR. Our study provides the first evidence linking c-Met, TIGAR and NADPH regulation in cancer cells, suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in cancer treatment.