Study ‘sheds light’ on critical step in RAS-driven cancers

Results of a recent study suggest how two oncogenic proteins—KRAS and RAF kinase—interact, and the structure of this protein-protein complex provides a blueprint for designing new inhibitors that could help prevent RAS-driven cancers. 

A graphic image of a biological structure
Surface representation of the structure of an oncogenic mutant of KRAS (colored pink) in complex with RAS-binding domains (colored cyan and green) of RAF1 Kinase. The GMPPNP bound to oncogenic KRAS mutant is shown in ball-and-stick representation. Image from Dhirendra Simanshu.

The KRAS gene provides instructions for making the KRAS protein that is part of a signaling pathway. The protein relays signals from outside the cell to the cell's nucleus. 

KRAS interacts with the effector protein RAF kinase, which helps regulate the activity for normal cell functions. Mutations in these two proteins are responsible for millions of cases of human cancer. More than 20 to 30 percent of all cancers can be traced to the RAS family of genes.  

“In this study, we provide for the first time how KRAS interacts with RAS-binding and membrane-interacting cysteine-rich domains of RAF kinase,” said Dhirendra Simanshu, Ph.D., principal scientist at the Frederick National Laboratory for Cancer Research and head of the RAS Structural Biology Group within the National Cancer Institute’s RAS Initiative. 

In Nature Communications, Simanshu and his team, in collaboration with Frank McCormick, Ph.D., and his team at the University of California, San Francisco, published structural and functional insights into the interaction between the wild-type and oncogenic mutant of KRAS with the RAS-binding domains of RAF kinase. McCormick is a consultant to FNL on the RAS Initiative. 

“This new study sheds light on the mechanism by which RAS activates RAF, a critical step in RAS-driven cancers.” McCormick said. “It revises a long-held view of how these proteins interact with each other and with the plasma membrane and provides exciting new opportunities for therapeutic intervention that were not possible previously.”   

Simanshu said the KRAS-RAF complex structure provides new therapeutic approaches to prevent RAS-mediated RAF activation to treat RAS-driven cancers.