In a recent study published in Science Signaling, titled “Phosphorylation of FADD by the kinase CK1α promotes KRASG12D-induced lung cancer”, a team of researchers from the University of Michigan Comprehensive Cancer Center, investigated the different players within the KRAS signaling pathway to understand potential targets for lung cancer therapies.
Even though there have been several studies aimed at targeting the KRAS gene for the treatment of lung cancer, so far the development of an effective therapy has been unsuccessful.
In their study, the team identified a protein, named FADD, that can uptake a phosphate for a specific amino acid when KRAS is active, a procedure called phosphorylation. Researchers used two engineered mouse models of lung cancer: one that overexpressed KRAS but did not express FADD in their cells and another that did not express KRAS but had normal levels of FADD in its genome.
The results showed that mice deficient for the FADD gene (deleted) did not develop lung tumors, even though they carried an active form of the KRAS gene.
It is known that FADD becomes phosphorylated through the action of CK1-alpha protein. As such, the research team used the KRAS mouse model and knocked-out CK1-alpha from the animal’s genome, leaving FADD untouched. Surprisingly, the results demonstrated that without CK1-alpha, FADD cannot become phosphorylated and looses its capacity to induce lung tumors in these mice, despite the presence of activated KRAS.
“We don’t have effective ways of targeting KRAS directly, so we have to go downstream to attack. This study shows that casein kinase 1-alpha is a bona fide target for treatment of KRAS-mutated lung cancer,” study author Alnawaz Rehemtulla, Ph.D., Ruth Tuttle Freeman Research Professor of radiation oncology and radiology and co-director of the Center for Molecular Imaging at the University of Michigan Medical School, said in a news release. “Figuring out how KRAS causes cells to divide is important and gives us potential avenues for blocking the downstream activity and inhibiting lung tumor growth,” Dr. Rehemtulla added.