Wang, Y, Ngo, VN, Marani, M, Yang, Y, Wright, G, Staudt, LM et al.. Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells. Oncogene 29: 4658-4670

Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, UK.
Oncogene (Impact Factor: 8.56). 08/2010; 29(33):4658-70. DOI: 10.1038/onc.2010.218
Source: PubMed

ABSTRACT Activating mutations in the KRAS gene are among the most prevalent genetic changes in human cancers. To identify synthetic lethal interactions in cancer cells harbouring mutant KRAS, we performed a large-scale screen in isogenic paired colon cancer cell lines that differ by a single allele of mutant KRAS using an inducible short hairpin RNA interference library. Snail2, a zinc finger transcriptional repressor encoded by the SNAI2 gene, was found to be selectively required for the long-term survival of cancer cells with mutant KRAS that have undergone epithelial-mesenchymal transition (EMT), a transdifferentiation event that is frequently seen in advanced tumours and is promoted by RAS activation. Snail2 expression is regulated by the RAS pathway and is required for EMT. Our findings support Snail2 as a possible target for the treatment of the broad spectrum of human cancers of epithelial origin with mutant RAS that have undergone EMT and are characterized by a high degree of chemoresistance and radioresistance.

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Available from: Yihua Wang, Mar 18, 2014
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    • "Direct inhibition of RAS activity has not met with great success (Downward, 2003), but targeting of downstream signalling molecules (such as RAF and MEK) holds promise (Montagut and Settleman, 2009). In addition, synthetic lethality screens have identified potential targets selective to RAS mutant cells (Wang et al., 2010). We did not find statistically significant differences in the CTL recognition of H Mu and H WT cells. "
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    • "Targeting STK33 through HSP90 inhibition in KRAS mutant cancers | Azoitei et al. regulators, and adhesion molecules (Singh et al., 2009; Scholl et al., 2009; Luo et al., 2009; Barbie et al., 2009; Puyol et al., 2010; Wang et al., 2010; Vicent et al., 2010). Although these molecules represent promising therapeutic targets, in principle , no specific inhibitors exist for most of them. "
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    ABSTRACT: Previous efforts to develop drugs that directly inhibit the activity of mutant KRAS, the most commonly mutated human oncogene, have not been successful. Cancer cells driven by mutant KRAS require expression of the serine/threonine kinase STK33 for their viability and proliferation, identifying STK33 as a context-dependent therapeutic target. However, specific strategies for interfering with the critical functions of STK33 are not yet available. Here, using a mass spectrometry-based screen for STK33 protein interaction partners, we report that the HSP90/CDC37 chaperone complex binds to and stabilizes STK33 in human cancer cells. Pharmacologic inhibition of HSP90, using structurally divergent small molecules currently in clinical development, induced proteasome-mediated degradation of STK33 in human cancer cells of various tissue origin in vitro and in vivo, and triggered apoptosis preferentially in KRAS mutant cells in an STK33-dependent manner. Furthermore, HSP90 inhibitor treatment impaired sphere formation and viability of primary human colon tumor-initiating cells harboring mutant KRAS. These findings provide mechanistic insight into the activity of HSP90 inhibitors in KRAS mutant cancer cells, indicate that the enhanced requirement for STK33 can be exploited to target mutant KRAS-driven tumors, and identify STK33 depletion through HSP90 inhibition as a biomarker-guided therapeutic strategy with immediate translational potential.
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