UT Southwestern investigators develop new strategy to classify cancers caused by KRAS mutations

UT Southwestern Medical Center researchers have developed a classification for cancers caused by KRAS, the most frequently mutated gene in cancer, that could eventually help oncologists choose more effective, customized cancer therapies.

That new strategy is based on models that researchers developed to classify cancers caused by KRAS (Kirsten rat sarcoma viral oncogene homolog) 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 subclassifying KRAS-mutant cancers so they can be treated more effectively, using therapies that are tailored to each mutation," said Dr. Kenneth Westover, Assistant Professor of Radiation Oncology and Biochemistry. "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 findings are available in Molecular Cancer Research, a journal of the American Association for Cancer Research.

KRAS is one of the main members of the RAS family. About a 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.

Specific KRAS mutations dominate in particular cancer types, giving rise to the notion that certain KRAS mutations may have distinct biological activities. Laboratory and clinical data support this hypothesis.

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.

"We attempted to use the observed structural changes to explain these differences in biochemical behavior.  By integrating our data, we have proposed a biochemical classification scheme to predict the propensity of different KRAS mutants to signal through RAF kinase. If validated, our model could have value for selecting targeted therapies for cancer patients with specific KRAS mutations," said Dr. Westover.

Members of the Westover lab plan to continue this line of work by testing their models in more complex experimental systems, such as genetically engineered cancer cell lines.