Pancreatic cancer is a leading cause of cancer-related death, with a five-year survival rate of 13%.
The high mortality is largely due to a lack of effective therapy options.
In a recent paper, published in Nature , researchers from the University of Michigan have discovered that simultaneously targeting PIKfyve and KRAS-MAPK can eliminate tumors in preclinical human and mouse models.
Pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, is challenging to treat because of the cellular environment.
"Pancreatic tumors are predominantly composed of non-cancer cells. In some patients, only 10% of the tumor is made up of the malignant cells," said Maisel Endowed Professor of Oncology Costas Lyssiotis, member of the Rogel Cancer Center and co-director of the Rogel and Blondy Center for Pancreatic Cancer.
"Even though these malignant cells don't have access to blood-derived nutrients because of dysfunctional blood vessels, they survive by turning on different processes."
These processes include recycling pathways, using nutrient transporters and evading the immune system.
Lysosomes, which are responsible for breaking down and recycling worn-out cell parts, play a key role in helping malignant cells thrive.
"Although the lysosomes are an attractive target, there are no medicines that work against them for pancreatic cancer," Lyssiotis said.
In the current study, the researchers focused on PIKfyve, an enzyme that has been identified as a lysosomal target for other cancer types, including blood malignancies.
"Even though PIKfyve inhibitors have cleared phase 1 clinical trials for other cancers, it was unclear how they worked to decrease tumor development and growth and whether they would work for pancreatic cancer," said Caleb Cheng, a graduate student in the Lyssiotis and Chinnaiyan lab, and the lead author on the study.
Using genetically engineered mouse models, the team showed that mice lacking PIKfyve developed cancer to a lesser extent compared to the mice that had PIKfyve.
Additionally, mice treated with PIKfyve inhibitors, apilimod and ESK981, had lower cancer growth after 10 weeks.
To understand how PIKfyve drives lysosomal processes in pancreatic cancer cells, researchers used human cell lines to identify which genes were affected by PIKfyve inhibitors.
"Lysosomes degrade molecules in the cell and use the resulting products to either make useful proteins or convert them into energy," Cheng said.
"We showed that lysosomes need PIKfyve to recycle fats. If we inhibit PIKfyve, the cells are now forced to make their own fats, and the relevant genes are turned on."
The team demonstrated that tumor cells make new fat through the KRAS-MAPK pathway.
"KRAS is the master regulator of pancreatic cancer, and new medicines are now in clinical trials to bring down this kingpin," Lyssiotis said.
While the implementation of KRAS inhibitors marked a major milestone for the field, cancer cells treated with KRAS inhibitors eventually became resistant.
This illustrates the need for combination approaches, further illuminating the potential of PIKfyve inhibitors.
"We definitively demonstrated the critical role of the PIKfyve gene in KRAS-driven pancreatic cancer," said Yuanyuan Qiao, research assistant professor of translational pathology, an author on the study.
In several state-of-the-art preclinical models, this combination therapy completely cured mice of pancreatic cancer.
"The most exciting aspect of our findings is the discovery of a novel strategy to rewire lipid metabolism and significantly enhance the efficacy of KRAS inhibitors—therapies already approved for pancreatic cancer treatment," said S.P. Hicks Endowed Professor of Pathology and Urology Arul Chinnaiyan, member of the Rogel Cancer Center.
The team is now working to find a way to eliminate the tumors.
"These cancer cells have perfected their ability to develop backup pathways, all of which we have tried to shut down in this study," Lyssiotis said.
"We believe that recruiting the immune system to target the surviving tumors will be the missing piece of the puzzle."
