A new study from University of North Carolina Lineberger Comprehensive Cancer Center researchers reveals important findings about how a common genetic mutation in pancreatic cancer works to drive tumor growth.
In the journal Cancer Discovery, researchers led by UNC Lineberger’s Channing Der, PhD, and Aaron Hobbs, PhD, reported details of the role of a particular mutation called KRAS G12R in pancreatic cancer, and therapeutic strategies that might work for this mutation type.
The study reflects a shift in the way researchers approach KRAS mutations in pancreatic cancer. By studying unique differences in DNA mutations within the same gene, researchers are working to uncover the unique, mutation-specific mechanisms that drive cancerous growth. This could potentially lead to different therapeutic strategies for each mutation type.
“The different properties of KRAS G12R may render pancreatic cancers with this mutation responsive to therapies that otherwise are not expected to work on other pancreatic cancers with other KRAS mutations,” said Der, who is a UNC Lineberger member and Kenan Distinguished Professor in the UNC School of Medicine Department of Pharmacology.
Efforts to target KRAS gene mutations
No effective therapies have been available to target mutations in the KRAS gene directly, although this gene is commonly mutated in cancer.
However, there are now therapies entering clinical trials that target a specific KRAS mutation called KRAS G12C. While prevalent in lung cancer, the KRAS G12C mutation is rare in pancreatic cancer.
Meanwhile, another mutation, KRAS G12R, is rare in lung and colorectal cancers, but is the third most common KRAS mutation in pancreatic ductal adenocarcinoma. The KRAS G12R mutation results in unique changes to the KRAS protein structure, the researchers found.
“For nearly four decades, the cancer research community has searched for a therapy for all KRAS mutant cancers, and has failed,” Der said. “Now, an emerging concept in targeting mutant KRAS for cancer treatment is that there may be distinct therapies for distinct KRAS mutations. This is a change from the idea that all KRAS mutant cancers will be sensitive to the same therapies.”
How does KRAS G12R work to drive pancreatic cancer?
In the study, researchers made important discoveries for the way that mutations in KRAS G12R work to drive pancreatic cancer. Insulin, which is produced in the pancreas, could be coordinating with this mutant protein to help unregulated cell growth.
“We provided an explanation for why KRAS G12R is found nearly exclusively in pancreatic cancer,” said Aaron Hobbs, PhD, research assistant professor in the UNC School of Medicine Department of Pharmacology and the study’s first author.
Furthermore, their study suggests a possible therapeutic strategy effective against pancreatic cancers with the KRAS G12R mutation. They found evidence that these cancers are sensitive to an investigational treatment that works by blocking the cell’s ability to get energy by recycling nutrients, along with other energy sources.
Der’s lab uncovered that investigational strategy earlier this year. The new study uncovers another potential application for this treatment type in KRAS G12R mutant pancreatic cancer tumors. “The great thing about this potential therapy is that it appears that so far, it’s going to be mutation independent,” Hobbs said.
Authors and Disclosures
In addition to Der and Hobbs, other authors included: Nicole M. Baker, Anne M. Miermont, Ryan D. Thurman, Mariaelena Pierobon, Timothy H. Tran, Andrew Anderson, Andrew M. Waters, J. Nathaniel Diehl, Bjoern Papke, Richard G. Hodge, Jennifer E. Klomp, Craig M. Goodwin, Jonathan M. DeLiberty, Junning Wang, Raymond Ng, Prson Gautam, Kirsten L. Bryant, Dominic Esposito, Sharon L. Campbell, Emanuel F. Petricoin III, Dhirendra K. Simanshu, Andrew J. Aguirre, Brian M. Wolpin, Krister Wennerberg, Udo Rudloff and Adrienne D. Cox.
The study was supported by the National Cancer Institute, the Department of Defense, the Lustgarten Pancreatic Cancer Foundation, and the Pancreatic Cancer Action Network. Individual researchers were supported by the Pancreatic Cancer Action Network/AACR, the National Cancer Institute, the Lustgarten Foundation, Dana-Farber Hale Center for Pancreatic Cancer Research, The Doris Duke Charitable Foundation, Debbie’s Dream Foundation, the American Cancer Society, the Slomo and Cindy Silvian Foundation, the Deutsche Forschungsgemeinschaft and the Centers for AIDS Research.
Disclosures: Der is a consultant/advisory board member for Mirati Therapeutics and Deciphera Pharmaceuticals. Der has received research funding support from Mirati Therapeutics and Deciphera Pharmaceuticals. Der has consulted for Eli Lilly and Ribometrix. Cox has consulted for Eli Lilly. Aguirre has consulted for Oncorus Inc. Arrakis Therapeutics and Merck & Co. Inc. Aguirre has received research funding support from Mirati Therapeutics and Deerfield Inc. Wolpin and consulted for BioLineRx, Celgene, G1 Therapeutics and GRAIL. Wolpin has received research funding support from Celgene and Eli Lilly.