Genes are segments of DNA that contain instructions for making a protein. The #KRAS gene serves as a blueprint to produce the KRAS protein, involved in a mechanism that initiates cell division. Uncontrolled activation of KRAS leads to cell proliferation and growth, resulting in cancer. Mutations in the KRAS gene are responsible for nearly 90% of pancreatic cancers, 40% of colorectal cancers and 35% of lung cancers. One in two men and nearly one in three women will develop cancer in their lifetime. In at least one in 10 cases, the tumor is driven by mutations in the KRAS gene, which was discovered in 1982 but is so complex that the scientific community has spent four decades trying to find its Achilles' heel. A team from the Centre for Genomic Regulation in Barcelona has finally produced a complete map of its weaknesses. Their article was published in the prestigious journal Nature last December.
For several decades, it seemed impossible to target this protein with drugs. This was due to allosterism, a phenomenon dubbed "the second secret of life" by French biologist Jacques Monod, who won the Nobel Prize in Medicine in 1965 for its discovery. The first secret comes from DNA and Monod realized that proteins have hidden switches that change their function. Finding these switches is a challenging task - for example, the water molecule is made up of only two hydrogen atoms and one oxygen atom (H2O), whereas the KRAS protein is made up of 939 carbon atoms, of which 1,516 are hydrogen atoms, 260 are nitrogen atoms, 291 are oxygen atoms, and 10 are sulfur atoms. This chemical giant has been impenetrable for decades.
The researchers used a novel method to assess the effect of 26,000 mutations on protein structure, rather than the dozens that have been the norm with previous tools. Their findings confirm a previously recognized weakness that is being addressed by #sotorasib and #adagrasib, the two drugs are the only approved drugs with the ability to inhibit the KRAS protein. In addition, the new map reveals another unknown Achilles' heel: the so-called tumor necrosis factor 3.
Planning and controlling expert
2moWas Nibrin (protein associated with the repair of double strand breaks, known as NBN or NBS1, part of MRN complex) included in this model?