Researchers have identified a new vulnerability in pancreatic ductal adenocarcinoma, the most common and aggressive type of pancreatic cancer, by focusing on transcription–replication conflicts.
In cancer cells, the machinery that reads genes and the machinery that copies DNA can collide, causing stress and DNA damage. These collisions are especially frequent in pancreatic cancer cells with KRAS mutations, which occur in about 95% of patients. While this stress destabilizes the cells, it also makes them highly dependent on survival mechanisms that handle these collisions.
An experimental drug, AOH1996, exploits this weakness by targeting the cellular conflicts, killing cancer cells while mostly sparing healthy ones. In preclinical studies with mice and human tumor organoids, the drug slowed tumor growth and extended survival. Early results from a small human pilot study were promising, with two patients showing shrinkage of liver metastases by up to 49% after two months of oral treatment. This approach, targeting the downstream effects of KRAS rather than the mutation itself, offers a new strategy for one of the deadliest cancers.