Scientists have unveiled the mechanism of action behind a genetic variant linked to longer survival and better treatment responses in patients with pancreatic cancer. Published in Cancer Research, these findings open up new opportunities for the development of targeted therapies and prognostic biomarkers for a form of cancer known for its aggressiveness.
About 95% of pancreatic tumors are driven by mutations in the KRAS gene, which drive fast tumor growth and metastasis as well as treatment resistance. However, approximately 15% of these patients carry a KRAS variant known as G12R, which is associated with more favorable outcomes, especially when chemotherapy is administered before surgery.
“It’s always been a peculiar mutation,” said Aaron Hobbs, PhD, assistant professor at the Hollings Cancer Center of the Medical University of South Carolina (MUSC) and senior author of the study. “Clinicians could see the difference in patient outcomes, but the molecular explanation just wasn’t there.”
To investigate the mechanism of action of this genetic variant, Hobbs and colleagues compared its effects on multiple disease models including mice, human cells, and patient-derived xenografts. Surprisingly, results showed that, unlike mice carrying other KRAS mutations, only 10% of mice with G12R mutations developed pancreatic cancer.
Further experiments revealed that while most KRAS mutations activate both the PI3K and ERK pathways in mice, G12R only activates the ERK pathway. This uncovered a key difference between mice and humans, namely the fact that mice require the activation of both signaling pathways to develop pancreatic tumors.
“When you inhibit KRAS in the mouse, you get a double hit,” said Hobbs. “But in humans, you only hit one pathway. That may be why some therapies work great in mice but underperform in human patients.”
Although the G12R mutation was found to activate the ERK pathway, this variant resulted in fewer of these proteins reaching the nucleus, where they activate genes that drive tumor growth. This led tumors to grow more slowly and behave less aggressively overall.
Pancreatic tumors are known for forming a dense shell made of collagen fibers that can prevent chemotherapy from reaching the tumor. However, tumors carrying the G12R variant were found to produce significantly less collagen than those carrying other KRAS mutations, and their collagen had a distinct structure making it looser and less rigid.
“In pancreatic cancer, the tumor itself can be tiny. Most of what you see is the stromal shell surrounding it,” said Rachel Burge, PhD, medical student at MUSC and lead author of the study. “Being able to separate the tumor from its environment helped us see differences no one had identified before.”
Finally, G12R tumors were reported to have reduced mobility, which in turn limited disease progression and metastasis. Altogether, these results could explain why this genetic variant is linked to better treatment responses, supporting the use of G12R as a prognostic biomarker in pancreatic cancer.
“If we can identify patients whose tumors carry KRAS G12R, we may be able to approach their care differently,” said Hobbs. “These tumors may be more sensitive to certain treatment sequences, and the biology gives us clues as to why.”
Furthermore, the study offers new opportunities for the development of therapeutic strategies that target the unique weaknesses of pancreatic tumors carrying G12R variants. Some examples could include blocking ERK from entering the nucleus, reducing cell mobility or disrupting collagen production in the tumor microenvironment.
“This study doesn’t solve the problem today,” Hobbs concluded, “but it lays the groundwork for how we could potentially improve survival for pancreatic cancer patients in the future.”
