Signaling pathways that suppress oncogenic ras
Authors: Frank McCormick
Journal: Cancer Research (2008)

SY25-03   Pathways regulated by oncogenic mutants of Ras are potential targets for therapeutic intervention. Compounds targeting the Raf/MAPK and PI 3’ kinase pathways are being tested in the clinic. Sorafenib, a drug approved for treatment of advanced hepatocellular carcinoma, as well as renal cancer, has been shown to be more effective on hepatocellular carcinomas with high levels of P-ERK (1), consistent with its ability to inhibit Raf kinase activity. While hepatocellular carcinomas do not typically contain mutations in RAS or RAF genes, high levels of Raf kinase signaling have been reported, possibly through loss of function of Sprouty-related proteins (2). On the other hand, Sorafenib failed to show clinical activity in melanomas expressing V600E activating mutations in BRAF. The basis of this observation will be discussed. Do date, the clinical effects of targeting PI 3’ kinase or Akt directly are not known. An mTOR inhibitor, Temsirolimus, has been approved for treatment of renal cell cancer, however, and other compounds targeting mTOR and related proteins are under development.  To identify other potential targets downstream of Ras, we are investigating intrinsic signaling pathways that appear to regulate signaling from Ras. One of these is driven by signals from activated ephrin receptors. These signals block Ras activation of MAPK and PI 3’ kinase pathways. As a result, the transformed phenotype of cancer cells can be reversed, despite the presence of mutant KRSAS or, in some cases, mutant BRAF (3). Potential mechanisms for these effects will be discussed. In addition, clinical responses to EGF-R inhibitors suggest that these receptors have a growth-suppressing effects in tumors with mutant KRAS. This unexpected result has major implications for cancer therapy using kinase inhibitors, and suggests signaling relationships that had not been previously recognized, even in a well studied pathway such as EGF-RAS. Recently, we identified a new step in this pathway by showing that signaling from EGF-R, and other receptors, to MAPK required co-recruitment of SCOC2/PP1C to the plasma membrane, through activation of R-Ras. As a result, negative regulatory phosphorylation sites on Raf kinase are removed, allowed efficient signal transmission.  It has been shown in mouse models of cancer that normal Ras proteins block oncogenic Ras activity. Some of these effects might be mediated by proteins of the Sprouty/SPRED family, which have also been shown to interfere with Ras activity, at least in the Raf kinase effector pathway. The potential importance of these pathways will be discussed in the context of targets for cancer therapy.   References   1. Abou-Alfa GK, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Onc 2006; 24:4293-300  2. Yoshida T., et al. Spreds, inhibitors of Ras/Erf signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. Oncogene 2006;25; 6055-66  3. Macrae M., et al. A conditional feedback loop regulates Ras activity through EphA2. Cancer Cell 2005; 8;111-8