It has been proposed that amplified c-Met drives the activity of EGFR family members thoroughly and that mutated and amplified EGFR can drive c-Met activity (Guo et al, 2008). Mutual or unidirectional interaction between EGFR and MET activation has been reported in several cell lines (Bergstrom et al, 2000; Jo et al, 2000; Reznik et al, 2008). It is thought that either c-Met or EGFR stands at the top of the hierarchy of the downstream signalling pathway governed by the two molecules in a subset of cancer. Collectively, it seems reasonable that efficient molecular therapy for CC should target multiple kinases such as c-Met, EGFR, and VEGFR. c-Met activation is regarded as one of the molecular mechanisms involved in the acquisition of resistance to anti-EGFR therapy, as activation of the alternative RTK pathway would bypass the EGFR pathway (Dempke and Heinemann, 2009).
Therefore, inhibition of c-Met, either alone or in combination with an EGFR inhibitor, may be clinically beneficial in the setting of EGFR inhibitor resistance (Eder et al, 2009). Several studies have focused on combination therapy with c-Met inhibitors and agents targeting EGFR family members (Toschi and Janne, 2008). In conclusion, c-Met overexpression is significantly correlated with overexpression of EGFR in CC and with prognosis in IHCC. Further molecular investigation of the interaction between EGFR and c-Met in this fatal disease is urgently needed. Acknowledgments This work was supported in part by the Foundation for Promotion of Cancer Research (FPCR), Japan, and a grant-in-aid for the Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare, Japan.
MM is a recipient of a Research Resident Fellowship from the FPCR.
Atherosclerosis is a dynamic process driven by both inflammation and hyperlipidaemia, and hence treatment should target both aspects of this disease. The current therapies to treat atherosclerosis primarily target hyperlipidaemia. However, different studies have shown that a substantial residual cardiovascular risk remains, even with very aggressive reductions in levels of low-density lipoprotein (LDL)-cholesterol (Baigent et al., 2005). Therefore, new therapies focusing on this unmet need are highly desirable. The liver X receptors (LXR�� or NR1H3 and LXR�� or NR1H2; nomenclature follows Alexander et al.
, 2009) are members of the nuclear receptor superfamily of transcription factors. It is now appreciated that both LXR isoforms function as intracellular sensors of cholesterol excess. LXR�� is predominantly expressed in tissues and cells that play important roles in lipid homeostasis, such as the liver, intestine, adipose tissue and macrophages, while LXR�� Dacomitinib is expressed in many cell types (Repa and Mangelsdorf, 2000). The natural ligands for both LXR isoforms include oxidized derivatives of cholesterol (i.e. oxysterols) (Janowski et al., 1996; Lu et al.