Dual targeting of ERK and PI3K pathways to impede pancreatic adenocarcinoma progression

Pancreatic ductal adenocarcinoma (PDAC) has a poor five-year survival rate of 13% primarily due to its late-stage detection and distant metastasis. Since surgical resection is only possible in about 10-20% of cases, chemotherapy is the sought after option. However, this strategy commonly results in toxicity and drug resistance in patients. Therefore, there is an increasing need for newer combination of drugs to reduce PDAC progression by targeting molecules involved in cell signaling pathways. The KRAS gene is mutated in almost 95% of the pancreatic cancers resulting in a hyperactivated K-ras protein, which activates downstream growth-promoting signaling pathways such as extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3 kinase (PI3K). Thus, we hypothesized that a combination of inhibitors targeting the kinases: ERK 1/2 and PI3K could lead to reduced PDAC cell proliferation. Our hypothesis was tested using a combination of SCH772984 (an ERK 1/2 inhibitor) and Pictilisib (class I PI3K inhibitor) on human PDAC cell lines: MIA PaCa-2 and PANC-1 and a patient-derived xenograft (PDX) cell line. Cell viability assays and clonogenic survival assays showed that both the drugs synergized with each other, reduced colony growth and cell proliferation compared to single inhibitor treatment. Additionally, western blotting experiments proved that both the inhibitors were able to engage with their targets: ERK 1/2 and AKT. Further steps will be encapsulating the drugs in a nanoparticle formulation to increase its solubility and stability and testing the drug combination in an animal model. This novel drug combination may help advance the field of treatment for addressing PDAC.