A new study is reshaping understanding of pancreatic ductal adenocarcinoma (PDAC), showing that PI3K signaling—key to tumor growth—can persist without direct activation by mutant KRAS. Researchers found that a common mutation, KRAS G12R, cannot activate PI3K, yet tumors still maintain strong pathway activity, suggesting an alternative mechanism is at work.
The study points to the loss of PTEN function as the main driver. Instead of being genetically deleted, PTEN is switched off through oxidation caused by cellular stress. This disables its normal role as a brake on PI3K signaling, allowing continuous tumor growth. At the same time, PDAC cells rely on multiple PI3K isoforms, meaning blocking just one is not enough to stop the cancer.
Researchers also found that nutrient-poor conditions inside tumors actually increase PI3K activity, helping cancer cells survive by scavenging external nutrients. These findings suggest that targeting KRAS alone may not be sufficient, and future treatments may need broader strategies that block PI3K activity and address the tumor microenvironment.