Researchers Develop New Classification Model for Cancer-Associated KRAS Mutations

Researchers in Texas are now reporting that there may be a smarter way to combat cancer-associated KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations and possibly attack specific tumor types in a new targeted manner. They are reporting that the use of biochemical profiling and sub classification of KRAS-driven cancers may lead to a more rational selection of therapies targeting specific KRAS isoforms or specific RAS effectors.

KRAS is one of the main members of the RAS family. About one-third of all human cancers, including a high percentage of pancreatic, lung, and colorectal cancers, are driven by mutations in RAS genes, which also make cells resistant to some available cancer therapies, according to the National Cancer Institute.

The UT Southwestern Medical Center researchers have developed a new classification for cancers caused by KRAS. They are investigating a new strategy based on models that the researchers developed to classify cancers caused by KRAS mutations, which cause cells to grow uncontrollably. Although KRAS-driven cancer mutations have long been a focus of cancer research, effective targeted therapies are not available.

“This work further supports the idea that not all oncogenic KRAS mutations function in the same way to cause cancer. The model we developed may help in sub classifying KRAS-mutant cancers so they can be treated more effectively, using therapies that are tailored to each mutation,” said Kenneth Westover, MD, who is an as Assistant Professor of Radiation Oncology and Biochemistry at the University of Texas Southwestern Medical Center, in a news release.¹ “Furthermore, this study gives new fundamental understanding to why certain KRAS-mutant cancers, for example those containing the KRAS G13D mutation, behave as they do.”

The researchers, who have published their findings in Molecular Cancer Research, have characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)–stimulated GTPase activities, and interactions with the RAS effector, RAF kinase. They report that KRAS G13D appears to show rapid nucleotide exchange kinetics compared with other mutants analyzed.²

In this study, the researchers evaluated eight of the most common KRAS mutants for key biochemical properties including nucleotide exchange rates, enzymatic activity, and binding activity related to a key signaling protein, RAF kinase. The researchers observed significant differences between the mutants, including about a tenfold increase in the rate of nucleotide exchange for the specific mutant KRAS G13D, highly variable KRAS enzymatic activities, and variability in affinity for RAF. They also determined high-resolution, three-dimensional X-ray crystal structures for several of the most common mutants, which led to a better understanding of some of the biochemical activities observed.

The researchers now plan to test their models in more complex experimental systems, such as genetically engineered cancer cell lines. 

References:

• UT Southwestern Medical Center. (2015). Researchers develop classification model for cancers caused by most frequently mutated cancer gene.
• Hunter JC, Manandhar A, Carrasco MA, et al. (2015). Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. Molecular Cancer Research, Sep;13(9):1325-35.