A team of Northwestern investigators has discovered novel molecular underpinnings of a common oncogenic mutation in cancer, findings that may inform the development of new therapeutic strategies, according to findings published in Nature Chemical Biology.
Shana Kelley, PhD, the Neena B. Schwartz Professor of Chemistry, Biomedical Engineering, and Biochemistry and Molecular Genetics, was senior author of the study. Kelley is also the president of the Chan Zuckerberg Biohub Chicago.
One of the most commonly mutated oncogenes in cancer, KRAS mutations are seen in pancreatic cancer, colon cancer and non-small cell lung cancer, among others. Mutations of KRAS have long been targets of interest for the development of new cancer therapies, but structural changes caused by these mutations have made it particularly difficult to target and inhibit.
Previous research efforts have aimed to target one specific KRAS mutation, KRAS-G12C, which has shown promising results in treating tumors. These findings motivated Kelley’s team to investigate another KRAS mutation, KRAS-G12V, and identify genes that specially modulate KRAS-G12V protein levels that could then be therapeutically targeted.
“What we decided is that rather than trying to get a small molecule to attack those amino acids specifically, let’s try to find a gene or a protein that actually regulates the levels of that mutated protein,” Kelley said.
By conducting genome-wide CRISPR–Cas9-mediated knockout screens in wild-type and KRAS-G12V cell lines, the scientists discovered that cells expressing the gene ELOVL6 had lower KRAS-G12V protein expression.
They found that ELOVL6, a fatty acid elongase, is involved in the production of the cell plasma membrane, and the lipid that ELOVL6 helps produce is where KRAS-G12V “anchors” itself, Kelley said.
“When we hit this lipid elongase, it selectively took out the lipid that the mutated KRAS liked, and so then the mutated form of the protein falls off the membrane and it gets degraded and it gets kicked out of the cell,” said Kelley, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “That was the big discovery; very unexpected.”
Next, the scientists found that giving mice with KRAS-G12V-mutated tumors an ELOVL6-inhibitor demonstrated a reduction in tumor growth and improved survival.
These findings may inform the development of new mutation-specific therapeutic strategies for treating mutant KRAS-driven cancers, Kelley said.
“We were able to show that this was potentially a way that a new therapy could be created,” Kelley said. “We’re working now on a startup company where we’ll be able to take that forward and see if it’s a new approach for oncology.”
Xiyue Hu, PhD, a former graduate student in the Driskill Graduate Program in Life Sciences (DGP), was lead author of the study.
This study was supported by the Chicago Biomedical Consortium grant C201612025 and startup funds from Northwestern University.
