KRAS is one of the most common oncogenes found in cancers of the pancreas, colon and lung, and mutations in the KRAS gene often lead to poor disease prognoses. But drugs targeting KRAS mutations remain elusive.
A new study provides some clarity for future drug development efforts with its finding that the effects of different KRAS mutations are much more complicated than scientists initially believed.
The KRAS protein helps relay signals to the cell’s nucleus that control cell growth and death. Mutations of the glycine 12 amino acid of the KRAS protein can cause glycine to mutate into any one of six possible types of amino acids, leading to uncontrolled cell growth and cancer progression. Mutations in the same location of KRAS were previously believed to be equal in function, but discoveries made by a team led by scientists at the University of Eastern Finland suggest otherwise.
Using molecular dynamics simulations, the researchers assessed the frequency of KRAS G12X mutations and their underlying causes using more than 31,000 KRAS-mutated tumor samples. They found different mutations have various effects on protein dynamics and hence on protein function, according to the study, published in the journal PLOS Computational Biology.
For example, a local shift in G12X can be conveyed to other remote structural regions in KRAS, the team found. The G12A and G12S mutations displayed the most altered interaction pattern within the network. And while the other types don't appear to be significantly different from the normal protein, they also convey some level of aberrant interactions, the researchers reported.
The KRAS field has been littered with failures. AstraZeneca’s MEK inhibitor selumetinib, for one, failed in KRAS-positive non-small cell lung cancer in 2016 as it didn’t improve either progression-free or overall survival in a phase 3. In July of this year, the company said the drug also flopped in thyroid cancer.
Because scientists have had difficulties targeting KRAS directly, they have started to investigate other methods for combating the errant gene. Boehringer Ingelheim recently teamed up with Vanderbilt University to go after a protein called SOS, which activates the KRAS gene. That’s based on their work identifying promising compounds that bind to KRAS with high affinity. Scientists at New York University have previously uncovered a mutated gene called KEAP1 that works with KRAS to cause lung cancer.
The Finnish team now hopes its findings will give rise to new drug candidates that target malfunctioning KRAS in different ways. “In order to establish successful therapies against mutant KRAS-harboring tumors, these discrepancies between the G12X mutants need to be reconsidered thoroughly,” write the researchers in the study.