Ras mutations

Ras Mutations yielding hyperactive Ras protein are frequent in human cancers... 

Roy, N.K., Stabile, J., and Seeb, J.E. et al. (1999). High frequency of K-ras mutations in pink salmon embryos exposed to Exxon Valdez oil. Environmental Toxicology and Chemistry 18, 1521-1528. 

Ch. 25). This means that mutations in these proteins that result in alterations in their regulatory properties can lead to oncogenesis. Ras in particular has been implicated in several human cancers [32]. It has been estimated that as many as 30% of all human cancers contain mutations in one of the three Ras genes. While the frequency of Ras mutations in some types of human cancer is very low, its frequency in certain cancers, such as squamous cell carcinoma, lymphatic cancers and colorectal adenocarcinoma, is very high. 

Toxicity and effectivity studies have often been performed in rodent fibroblast cells containing oncogenic H-Ras. However, prenylation of K-Ras B and N-Ras are not as effectively blocked by the farnesyltransferase inhibitors as H-Ras [48] (see below). Thus normal cells may be less sensitive to these drugs because they express K-Ras 4B and N-Ras. In this context it should be noted that H-Ras mutations are relatively uncommon in human tumors [49]. Rather, the K-Ras gene is the most frequently mutated in solid human cancers, whereas N-Ras is prevalent in leukemias. Thus the preclinical evaluation of the farnesylation inhibitors has yet to be critically re-evaluated for trials in humans. 

Moser GJ, Robinette CL, Smart RC. 1993. Characterization of skin tumor promotion by mirex structure-activity relationships, sexual dimorphism and presence of Ha-ras mutation. Carcinogenesis 14(6) 1155-1160. 

The mechanistic basis of the anti-neoplastic activity of UDCA and the explanation for the significant difference in bioactivity of UDCA compared with DCA despite marked similarity in chemical structure remain unresolved. UDCA administration in healthy volunteers and colorectal adenoma patients has been demonstrated to decrease the proportion of DCA in aqueous phase stool. Therefore, one possible mechanism of the chemopreventative activity of UDCA is reduction of mucosal secondary bile acid exposure. Consistent with this idea, UDCA administration has been demonstrated to reduce the incidence of K-ras mutations and decrease Cox-2 expression in AOM-induced tumors, which is the opposite of the reported effects of DCA in the same model. However, it is clear that exogenous administration of UDCA has direct anti-neoplastic activity on human CRC cells in vitro, either alone or in combination with DCA, including anti-proliferative and anti-apoptotic effects, as well as induction of cell senescence. " ... 

S. Khare, S. Cerda, R. K. Wall, F. C. von Lintig, M. Tretiakova, L. Joseph, D. Stoiber, G. Cohen, K. Nimmagadda, J. Hart, M. D. Sitrin, G. R. Boss and M. Bissonnette, Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclo-oxygenase-2 expression in colon cancer, Cancer Res., 2003, 63, 3517. 

Matson, R.S., Oligonucleotide arrays for the detection of ras mutations, in Nonradio-active Analysis of Bio-Molecules, Kessler, C., Ed., Springer, Heidelberg, 2000, chap. 64. 

Ras, a historical proto-oncogene, is frequently mutated in many human cancers, including 90% of pancreatic cancers, 50% of colorectal cancers, 30% of lung cancers, and 15-30% of melanomas [10-12]. There are three Ras genes that encode four family members K-Ras (two alternatively spliced isoforms), H-Ras, and N-Ras. Mutations are most commonly found in K-Ras [13]. These mutations result in impaired GTP hydrolysis, which shifts the equilibrium toward GTP-bound active Ras, and results in constitutive intracellular signaling. 

In precHnical models, ARRY-142886 treatment results in either tumor regression or stasis in xenograft models of colorectal, non-small cell lung, pancreatic, breast, and melanoma cancers. Most of these cell lines contain either the B-Raf or K-Ras mutations. Complete inhibition of pERKl/2 formation in excised tumors from both HT-29 and BxPC3 studies was achieved 4 h after an oral dose of 20 mg/kg/day ARRY-142886 [114]. In a separate HT-29 study, a PK/PD relationship was established [115]. Twelve hours after a single 30 mg/kg oral dose of ARRY-142886, approximately 80% inhibition of ERKl/2 phosphorylation was observed with a corresponding plasma concentration of about 0.60 xg/ml. In the same study at 24 h, ERKl/2 phosphorylation was... 

Activating Ras mutations have been found in more than 25% of human tumors. However, a drug-like small molecule inhibitor for Ras protein is not currently available. Several synthetic lethal screens have been carried out using isogenic cell lines for Ras. Torrance et al. conducted a synthetic lethal screen of a library of about 30,000 compounds and identified some novel hits including... 

Porta, M., N. Malats, L. Guamer, et al. CA068 Association between coffee drinking and K -ras mutations in exocrine pancreatic cancer. PANKRAS 11 Study CA069 Group. J Epidemiol Comm Health 1999 53(11) 702-709. 

Wells. Investigation of the tobacco-specific carcinogen 4-(methylnitro-samino)-l-(3-pyridyl) l -butanone for in vivo and in vitro murine embryopathy and embryonic ras mutations. J Pharmacol Exp Ther 1998 287(3) 1128-1135. 

Thus, mutational activation of EGFR and K-Ras within the same tumor cell may result in senescence when pl6 or ARF activities have not been lost. Alternatively, EGFR and K-Ras mutations within the same tumor cell may trigger a strong apoptotic response... 

You, M., Wang, Y, Nash, B. Stoner, GD. (1993) lA-ras mutations in benzotrichloride-induced lung tumors of A/J mice. Carcinogenesis, 14, 1247-1249... 

Porta M, Malats N, Jariod M, Grimlat JO, Rifa J, Carrato A, Guamer L, Santiago-Silva M, Corominas JM, Andreu M, Real EX (1999) Serum levels of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer. Lancet 354 2125-2129... 

A Japanese study of DNA extracted from endometrial polyps in women treated with tamoxifen showed a threefold increase in K-ras mutations compared with the incidence in cases of spontaneous endometrial hyperplasia. These findings could support the hypothesis that the endometrial polyps will prove an early indicator for the development of endometrial carcinoma in such patients (86). 

Hachisuga T, Miyakawa T, Tsujioka H, Horiuchi S, Emoto M, Kawarabayashi T. K-ras mutation in tamoxifen-related endometrial polyps. Cancer 2003 98 1890-7. 

The catalytic glutamine at position 204 in Gail is a conserved feature in all functional Ga proteins, and in most members of the Ras superfamily (residue 61 in Ras). Mutations of this residue in Ga and Ras abolish GTPase activity, are constitutively active, and contribute to cellular transformation (Barbacid, 1987 Bourne et aL, 1991 Gilman, 1987). Further, GTPase activity of the... 

M. E. M., Wolf, B., Sabatini, L., Jett, J., Kohman, L., and Johnson, D. H. 2001. Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small cell cancer on E4592 A laboratory ancillary study on an eastern cooperative oncology group prospective randomized trial of postoperative adjuvant therapy. 7. Clin. Oncol. 79 448-457. 

In addition to Ras, a number of other proteins are known to be substrates for FTase (many of unknown identity or function, determined by 2-D gel shift experiments in the presence and absence of FTI) these may also play a part in determining relative susceptibility to FTase inhibition.46 In particular, RhoB, a farnesylated protein involved with the formation of actin stress fibers and cytoskeletal organization, has been implicated in the growth-inhibitory consequences of FTase inhibition.47,48 Another study using the FTI 19 found that growth inhibition in soft agar of a panel of human tumor cell lines correlated with the mutational status of the H-and N-Ras proteins, but not with K-Ras mutations.49 In this study also, cells with genetic defects in addition to ras were sensitive to FTase inhibition. 

Dammann R, Schagdarsurengin U, Liu L, et al. Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma. Oncogene 2003 22 3806-3812. 

Soper, S.A., Murphy, M.C., McCarley, R.L., Nikitopoulos, D., Liu, X., Vaidya, B., Barrow, 1., Bejat, Y., Ford, S.M., Goettert, 1., Fabrication of modular microsystems for analyzing K-ras mutations using LDR. Micro Total Analysis Systems, Proceedings 5th iTAS Symposium, Monterey, CA, Oct. 21-25, 2001. Kluwer Academic Publishers, Dordrecht, the Netherlands, 2001, 459-461. 

Mills NE, Hayes RB, Fishman CL, etal. 1994. Ras mutations in Chinese patients with benzene-associated and de novo acute leukemia. Abstracts Submitted To The 36th Annual Meeting Of The American Society Of Hematology, Nashville, Tennessee, USA, December 2-6, 1994. Blood 84(10 Suppl. 1) 47a. 

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