The K-Ras gene is found to be mutated in 30% of all tumors (human), but this rises to 90% or more in pancreatic cancer (ductal adenocarcinoma of the pancreas). It is considered an “oncogene” meaning a gene whose mutation typically initiates a cascade of proteins that signal for rapid cell growth and division – in this case by promoting an increased binding of the referent protein to GTP (guanosine triphosphate) and a reduced ability to convert GTP to GDP – thus potentiating cell proliferation and ameliorating signals for programmed cell death. As such the K-Ras mutation is one of the most powerful divers of cancer in human beings. And this is assumed to be especially true in pancreatic cancer. Though the K-Ras involvement in pancreatic cancer has been known for decades, direct approaches at altering this mechanism have largely proved elusive.
However, this past June the U.S. National Cancer Institute revealed that it will offer substantive ($10M) grants for scientists to target K-Ras. Also, a piece of exquisite research by Kevan Shokat and colleagues from the Howard Hughes Medical Institute at the University of California in San Francisco has given impetus to this mission. On November 20, 2013 in the journal Nature these researchers E-published an article on their work detailing their discovery of a specific compound that binds to the K-Ras protein known as G12C which tends to inhibit the effects of the mutated protein. G12C is the most common mutation of K-Ras whereby cysteine replaces glycine at position 12 of the protein – this mutation is found for example in more than 20,000 patients with lung and colorectal cancer annually in the U.S.
The investigators screened more than five hundred compounds – finally discovering one that binds to a previously unrecognized pocket (identified by crystallographic means) near G12C on the physical structure of the protein. The effect of the binding of this compound to the K-Ras protein appears to reduce the affinity of G12C for GTP, but not for GDP, thus allowing for reinstatement of the more normal (non-mutated) action of K-Ras.
This is a fascinating study that offers future promise for the treatment of pancreatic cancer.
Dale O’Brien, MD