Targeting KRAS in pancreatic cancer
The Kirsten rat adenosarcoma (KRAS) gene codes for a member of the RAS small GTP binding protein family. RAS small G proteins are activated when they interact with growth factor bound receptors. They are inactivated when they interact with G=protein associated proteins (GAP). GAPs activate hydrolysis of GTP to GDP. Mutations which prevent interaction with GAPs are responsible for a large percentage of pancreatic cancers (Zeitouni 2016). Daniel Zeitouni and others at the University of North Carolina, Chapel Hill, discussed the role of mutations in KRAS in pancreatic adenocarcinoma.
Zeitouni and others discuss different ways of stopping mutated KRAS that lacks the off switch. Some of these means might be small molecular inhibitors of KRAS as well as inhibitors of down stream and up stream signaling proteins. Small pieces of complementary RNA that interfere with KRAS mRNA translation into protein are also discussed.
Traditional means of fighting pancreatic cancer include preventing translation of KRAS mRNA into protein and inactivating the protein itself. mRNA transcripts for KRAS just don’t appear out of the blue. The KRAS gene resides on chromosome 12. DNA on chromosomes is condensed onto histones that are also modified by attaching small adducts such as the acetate and citrulline.
The KRAS gene, a different site of regulation
Transcription only occurs when other proteins bind to the promoter, a region upstream of the protein coding part of the KRAS gene.
Christine Kaiser and others in Lawrence Hurley’s group at the university of Arizona studied the ability of a benzophenanthridine alkaloid to dissipates the hairpin species and destabilizes the interaction of hnRNP K with the Mid-region i-motif. This same compound stabilizes the three existing KRAS G-quadruplexes.
Does inhibiting a mutant KRAS gene from being transcribed into mRNA in the first place sound like a good approach? Reglagene thinks so too.
I wrote this to get to know a local company as an example of skills I learned working for Ignyta. My preference would be to coauthor such narratives geared towards more lay audiences. Contact me if you are interested in discussing things.