RASG12D causes more Proliferation than RASG12V in Drosophila Pancreatic Cancer Models

Pancreatic cancer is the fourth leading cause of death in the United States. Over 95% of pancreatic cancer patients have activating mutations in the KRAS oncogene, suggesting that these mutant KRAS forms play a critical role in development of the disease. The most common mutations in KRAS are G12D and G12V missense mutations, but little is known about functional differences between them. Therefore, our objective is to compare the outcomes between KRASG12D and KRASG12V mutations in pancreatic cancer models. Using the Gal4‐UAS system, which allows the expression of transgenes in a specific tissue, we developed pancreatic cancer models in the fruit fly Drosophila. The patched promoter‐driven Gal4 transcription factor targeted the Drosophila RasG12D or RasG12V transgene to the midline of the fly wing epithelium. Using green fluorescence protein (GFP) as a marker for Ras‐expressing cells, we found that RASG12D directed more aggressive expansion of the patched domain than wild type or RASG12V wing epithelia. Oral dosing of trametinib—a MEK inhibitor that blocks signaling downstream of RAS—decreased proliferation of RASG12D expressing cells. These results indicate that trametinib could be a useful drug against RAS‐positive cells for RASG12D mutations. Future experiments include understanding the mechanisms by which RASG12D and RASG12V direct different phenotypes, and further developing novel treatments based on trametinib. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .