novel pancreatic cancer treatment

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.

Epidermal growth factor, EGF, KRAS, and pancreatic cancer
A. Epidermal growth factor binds to its receptor activating a cascade of events called signal transduction. Activated RAS is Guan osine triphsaphate (GTP.) B. G protein associated proteins cause the hydrolysis of GTP to GDP inactivating RAS. Mutated KRAS cannot be inactivated by GAPs

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.

mRNA, ribosome, G12C KRAS, active site inhibitor
KRAS mRNA transcripts are exported from the nuceaus where they are translated into protein by ribosomes. A portion of the translated protein (right) is shown in the white window. The yellow shaded region is the Glys12Cys activating mutation. To either side is GDP and a small molecule inhibitor.

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

chromosome 12, KRAS, promoter, RNA polymerase
Transcription of a gene from a chromosome is a complex process with many points 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.

3D structures of the KRAS promoter: additional ways of regulation

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.



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