KRAS mutations have been found in about 35% of colon carcinomas that mainly occur at codons 12, 13 and 61, resulting in a constitutively active form of KRAS Pacritinib SB1518 GTPase. Consequently, multiple RAS effector pathways that regulate fundamental biological processes such as proliferation, apoptosis, and cell motility, become activated and or deregulated. More specifically, mutant KRAS disrupts actin cytoskeleton and maintains motility in colon cancer cells. Likewise, BRAF, a major down stream effector of KRAS, is also considered an oncogene whose activating mutations appear in 70% of human malignant melanomas and in about 12 18% of human colon cancers. The most frequent BRAF mutation is at codon 600 that results in elevated kinase activity. Mutant BRAF may also interfere with organization of cytoskeleton and affect cell migration and invasion ability.

Key steps in invasion and metastasis are tightly regu lated or influenced by Inhibitors,Modulators,Libraries the Rho family GTPases, which may include alterations in cell adhesion, cell matrix, cell cell interactions and actin organization, ultimately leading to the acquisition of an invasive phenotype. Many studies have investigated the role of Rho GTPases in tumour progression showing their contribution in cancer initiation and progression, through the acquisi tion of uncontrolled proliferation, survival and escape from apoptosis Inhibitors,Modulators,Libraries as well as tissue invasion and the estab lishment of metastasis. Unlike KRAS and BRAF, mutations in RHO genes are extremely rare in tumours, but their expression and or activity is frequently altered in a variety of human cancers.

RhoA is frequently over expressed in cancer, while depletion of Rac1 strongly inhibits lamellipodia formation, cell migration and inva sion in carcinoma cells. Another Rho family gene, Cdc42 is also important for cell motility and able to induce a mesenchymal Inhibitors,Modulators,Libraries amoeboid transition in mela noma cells. Regulation of Rho GTPases is exten sively studied and it is well known that Inhibitors,Modulators,Libraries extracellular signal regulated kinase signaling is important for cell motility through Rho GTPases. PI3K pathway is also involved Inhibitors,Modulators,Libraries in Rho family signal transduction and affects properties like cell migration. Although a significant number of studies have analysed the role of Rho pathways in RAS induced transformation, very little is known about the differential regulation of Rho GTPases by RAS and BRAF oncogene, as well as their subsequent contribution in oncogene specific cell migra tion properties. In order to invade into other tissues, epithelial cancer cells must disrupt the integrity of epithelium and base ment membrane to enter the underlying stroma. This normally requires acquisition of a migratory phenotype, a process frequently the following site referred as epithelial to mesenchy mal transition.