Pancreatic cancer: factor responsible for resistance to new molecular therapies identified
The KRAS gene mutation is a defining feature of pancreatic ductal adenocarcinoma, the most common and aggressive form of pancreatic cancer, and drives its onset and progression. In recent years, the development of targeted drugs against the altered KRAS protein has opened up new therapeutic prospects. However, their effectiveness in clinical practice remains limited, as pancreatic cancer cells rapidly develop resistance mechanisms to these inhibitors.
A group of researchers from Sapienza University of Rome, led by Gian Luca Rampioni Vinciguerra of the Department of Clinical and Molecular Medicine, and from The Ohio State University (USA) identified the Fra-2 protein as a key factor regulating this resistance to pharmacological inhibition of KRAS.
More specifically, the results of the study, published in the prestigious international journal Proceedings of the National Academy of Sciences, revealed that Fra-2—a transcription factor that, under physiological conditions, regulates the cell’s response to stress—is abnormally activated in cancer cells exposed to treatment. By regulating gene expression, Fra-2 is also capable of profoundly reshaping the molecular architecture of cancer cells, making their proliferation independent of KRAS when the latter is pharmacologically inhibited, and thus effectively rendering the action of drugs designed to target it ineffective.
The research findings also suggest that Fra-2 could be a promising therapeutic target: laboratory studies showed that the combined inhibition of KRAS and Fra-2 can significantly enhance the effectiveness of treatments for the disease, opening up new avenues for the treatment of this cancer, which remains difficult to treat.
The study was carried out with the support of the AIRC Foundation and thanks to the multidisciplinary collaboration of several Italian centres of excellence, including the Agostino Gemelli University Hospital Foundation,Aviano Oncology Reference Centre, University of Verona and University of Modena and Reggio Emilia.
References: Rampioni Vinciguerra et al. Fra-2 controls the response to the KRAS inhibitor MRTX-1133 in pancreatic ductal adenocarcinoma (2026). PNAS
DOI: 10.1073/pnas.2601788123
Further Information
Gian Luca Rampioni Vinciguerra – Department of Clinical and Molecular Medicine
