Triple-drug therapy halts pancreatic tumors in mice

A three-drug combination that targets KRAS, a KRAS-related pathway and STAT3 eliminated pancreatic tumors in multiple mouse models and caused no major toxicity; researchers plan further preclinical testing and drug development.

Researchers report that a three-drug combination eliminated pancreatic tumors in several types of mouse models and produced no major toxic effects in the animals. Pancreatic cancer is a disease with a low five-year survival rate and is often linked to mutations in the KRAS gene. Prior work showed that blocking some KRAS-related pathways can shrink small tumors, but larger tumors often adapt by activating other routes. The new study identified STAT3 as a key backup pathway and tested a drug-based strategy to block KRAS, a KRAS-related pathway, and STAT3 at the same time. Key findings: - The combination therapy targeted KRAS, a KRAS-related pathway, and STAT3 and eliminated tumors in three mouse-model systems: implanted mouse tumors in the pancreas, genetically engineered mice, and mice carrying human tumor samples. - In treated animals, tumors did not return for at least 200 days, a longer period than typically seen with single-drug approaches in similar models. - The treated mice showed no major signs of toxicity, with body weight, blood counts, metabolic markers and organ health similar to placebo-treated animals. - The drug mix included afatinib, daraxonrasib, and an experimental STAT3 inhibitor; afatinib is FDA-approved for some lung cancers and daraxonrasib is undergoing clinical trials. - Researchers reported plans to test additional mouse models that carry other common KRAS mutations and to work on developing better drugs that act on the same pathways. Summary: The study found that a triple-pronged drug approach produced complete tumor regression and prolonged remission in several mouse models without obvious animal toxicity. Researchers say they will expand testing in other preclinical models and work on improved compounds; the timing and outcome of any human clinical testing are undetermined at this time.