Master Who's Afraid Of deacetylase inhibitor Dinaciclib

As described above, c MET signaling is an intri cate and very regulated method.

The c MET identified within this cell line contained a chromosomal rearrangement that fused the tyrosine kinase domain with the c MET proto oncogene to an upstream deacetylase inhibitor translocating promoter region. This rearrangement caused constitutive dimerization and therefore activation of the encoded protein. Expression of TPR MET in transgenic mice resulted in the development of multiple epithelial derived tumors. In humans, the TPR MET translocation has been found in both the precursor lesions of gastric can cers and in the adjacent normal mucosa, suggesting that this genetic lesion can predispose to the development of gastric carcinomas. Amplification of the c MET gene, with conse quent protein overexpression and constitutive kinase activation, has been reported in a number of human primary tumors.

Activating kinase domain mutations have subse quently been identified in a small number of other cancers. Mutations have also been identi fied in the c CBL binding PARP site of the juxtamem brane domain and in the HGF binding region of the Sema domain. In hered itary cancers, heterozygous mutations are usually accompanied by trisomy of the whole chromo some 7, suggesting that when only a single allele is mutated the mutation must be present in multiple copies to produce the full trans formed phenotype. Increased protein expression as a consequence of transcriptional Dinaciclib upregulation in the absence of gene amplification is the most frequent cause of constitutive c MET activation in human tumors, and has been reported in an ever growing number of carcino mas, including thyroid, colorectal, ovarian, pancreatic, lung and breast, to name a few.

The autocrine stimula tion of c MET has also been identified in cancer cells, and appears to be indicative of increased aggressiveness of tumors along with poor prognostic signs in cancer Dinaciclib patients. c MET as a target for therapeutic inhibition Although the development of c MET inhibitors will be discussed elsewhere in this supplement, here we consider the dual role c MET plays in both the development and progression of cancers, and how each could be targeted by c MET inhibitors.