National Health Research Institutes

Dual Precise Targeting
 the “Achilles Heel” in Pancreatic Cancer

March 4, 2024

Pancreatic cancer, a highly malignant tumor, ranks seventh in cancer-related mortality in Taiwan. Its incidence and mortality rates are nearly identical, underscoring the limited success in current pancreatic cancer treatments. Improving patient survival represents an unmet need in clinical medicine. In recent years, the application of next-generation sequencing has unveiled multiple highly mutated genes in pancreatic cancer, including K-RAS, TP53, CDKN2A, and SMAD4. Pancreatic tumors frequently harbor an additional genetic defect; however, the precise function of these less frequently mutated genes in the initiation and progression of pancreatic cancer remains elusive. Whether targeting these mutated genes can improve therapeutic efficacy in treating pancreatic cancer is also unclear.

Approximately 6–10% of pancreatic cancer patients harbor mutations in the RNF43 gene. RNF43 is a transmembrane protein and a crucial regulator in the WNT signaling pathway. Biologically, RNF43 is an E3 ubiquitin ligase that ubiquitinates and degrades the WNT receptor Frizzled to modulate stem cell differentiation and organ development. However, the role of RNF43 in pancreatic tumorigenesis and its downstream mediators are largely unknown.

A research team led by Distinguished Investigator Dr. Wen-Chun Hung of the National Health Research Institutes and Chair Professor Dr. Li-Tzong Chen of Kaohsiung Medical University found that RNF43-mutated pancreatic cancer cells are highly sensitive to MEK-MAPK pathway inhibitors. Following a global screening of potential upstream regulatory proteins of MEK, they identified B-RAF as a novel target protein of RNF43 and uncovered the molecular mechanism by which RNF43 regulates B-RAF. Molecular modeling prediction explains how phosphorylation and ubiquitination induce a structural change in the B-RAF protein.

Combining MEK inhibitors with WNT inhibitors showed a synergistic cytotoxic effect on RNF43-mutated pancreatic cancer cells, causing significant tumor reduction in animals. Analysis of clinical data from The Cancer Genome Atlas (TCGA) database also revealed a significant increase in B-RAF protein in pancreatic cancer patients with RNF43 mutations, supporting the team’s findings. The results of the study were published in a prestigious journal, Advanced Science. This study provides a new strategy for the treatment of pancreatic cancer and contributes to personalized precision medicine.