Combining Lysosomal Enzyme Inhibition with KRAS-MAPK Pathway Targeting Shows Promise for Pancreatic Cancer Treatment

Recent research from the University of Michigan has demonstrated that a dual therapeutic approach targeting both lysosomal enzymes and the KRAS-MAPK signaling pathway can effectively eradicate pancreatic tumors in preclinical models. Pancreatic ductal adenocarcinoma (PDAC), the most common and deadly form of pancreatic cancer, remains difficult to treat due to its complex tumor microenvironment, characterized by a high proportion of non-cancerous cells that support tumor survival.

The study highlights the role of lysosomes—cellular organelles responsible for degrading and recycling cellular waste—in supporting malignant cell survival despite poor nutrient supply caused by abnormal blood vessels. Researchers focused on PIKfyve, an enzyme involved in lysosomal function, which has previously been targeted in other cancer types. Genetic deletion or pharmacological inhibition of PIKfyve, using agents like apilimod and ESK981, significantly reduced tumor growth in mouse models.

Further investigations revealed that inhibiting PIKfyve disrupted lysosomal fatty acid recycling, compelling cancer cells to increase their own fat synthesis via the KRAS-MAPK pathway—an important driver of pancreatic cancer. While targeting KRAS itself has been a significant step forward, cancer cells often develop resistance to these inhibitors, emphasizing the need for combination therapies.

By simultaneously targeting PIKfyve and KRAS-driven metabolic processes, the researchers achieved complete tumor remission in several preclinical models. This approach rewires lipid metabolism within cancer cells and enhances the efficacy of existing KRAS inhibitors. The findings suggest that integrating lysosomal enzyme inhibition with pathway-specific treatments could offer a new, more effective strategy for managing pancreatic cancer.

The research team is optimistic about translating these findings into clinical trials and is exploring ways to harness the immune response to eliminate residual tumor cells, aiming to overcome resistance and improve patient outcomes. This innovative combination approach underscores the potential of targeting tumor metabolism alongside genetic pathways to fight this formidable disease.

Source: MedicalXpress