Abstract A1: SIAH E3 ligase as a novel anticancer drug target to inhibit RAS‐mediated tumorigenesis and metastasis in human cancer cells

The central importance of the ERBB/RAS signal transduction cascade has been well established in human cancer. As such, novel approaches to counteract activated ERBB/RAS signals constitute important measures to reverse tumorigenesis and metastasis in human cancers. Instead of targeting an upstream signaling module such as ERBB/RAS/MEK/MAPK/AKT/mTOR, we targeted the most downstream signaling module in the ERBB/RAS pathway called the SIAH‐dependent proteolytic machinery. SIAHs are the human homologs of Seven‐In‐Absentia (SINA), an evolutionarily conserved RING E3 ligase, an essential downstream signaling module and a critical “gatekeeper” required for proper Drosophila RAS signal transduction. Guided by the insights and principles learned from Drosophila RAS signaling pathway, we conducted preclinical studies to examine SIAH function in the context of RAS‐mediated tumorigenesis and metastasis in human cancer cells.We found that (1) SIAH is a novel biomarker for human cancer, i.e. it specifically decorates proliferating tumor cells (not stromal cells in the tumor microenvironment). SIAH expression is progressively and markedly upregulated as human cancer progresses to the advanced stages in human pancreatic, lung, breast and prostate cancers; and (2) inhibiting the proteolytic function of SIAH is highly effective to abolish tumorigenesis and metastasis in eight of the most aggressive human cancer cell lines known in the literature that include pancreatic cancer cells (MiaPaCa and Panc‐1), lung cancer cells (A549), invasive breast cancer cells (MDA‐MB‐231, MDA‐MB‐468 and MDA‐MB‐435) and hormonal‐refractory prostate cancer cells (PC‐3 and DU‐145) in soft agar as well as in athymic nude mice. These findings suggest that SIAH may be an attractive new therapeutic target for novel anti‐RAS and anti‐cancer therapy in human cancer. As a highly evolutionarily conserved E3 ligase and consistent with its “gatekeeper” function identified in the ERBB/RAS signaling pathway, SIAH is well positioned to become a next‐generation and potent anticancer drug target to block the tumor‐promoting RAS pathway and to treat the most aggressive types of human cancers. “Using anti‐SIAH molecules to block active RAS signaling in human cancer” may be another example of “from the bench [basic science from fruitflies (model organism) to human cancers] to the bedside story [translational medicine in the near future]”. Anti‐SIAH‐based anticancer strategy may aid in expanding our arsenal of novel anticancer therapies. By attacking the oncogenic ERBB/RAS pathway using multi‐pronged synergistic inhibitions at upstream (EGFR/HER2 membrane receptors), midstream (RAS/RAF/MEK/mTOR) and downstream (SIAH E3 ligase) signaling modules in parallel, we may be in a great position to halt the genesis, progression and metastasis of the most aggressive and lethal types of human cancers. If successful, we hope to translate our findings to the cancer clinics to treat many cancer patients with metastatic diseases in the future. Citation Information: Cancer Res 2009;69(23 Suppl):A1.