AUM302, a novel triple kinase PIM/PI3K/mTOR inhibitor, is a potent in vitro pancreatic cancer growth inhibitor

• Published in: PloS one Vol. 18; no. 11; p. e0294065
• Main Authors: Ingle, Komala, LaComb, Joseph F, Graves, Lee M, Baines, Antonio T, Bialkowska, Agnieszka B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.11.2023; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; AKT protein; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Apoptosis; Biology and Life Sciences; Cancer; Cancer therapies; Carcinoma, Pancreatic Ductal - pathology; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell survival; Cell viability; Chemoresistance; Chemotherapy; Comparative analysis; Computer and Information Sciences; Drug therapy; Engineering and Technology; Gemcitabine; Growth Inhibitors - pharmacology; Health aspects; Humans; Kinases; Medical prognosis; Medicine and Health Sciences; Metabolism; Metastasis; Mutation; Pancreatic cancer; Pancreatic Neoplasms - pathology; Penicillin; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphorylation; Prostate cancer; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Radiation therapy; Research and Analysis Methods; Testing; TOR protein; TOR Serine-Threonine Kinases; Tumors; United States; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0294065

Pancreatic cancer is one of the leading causes of cancer deaths, with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype. Advanced stage diagnosis of PDAC is common, causing limited treatment opportunities. Gemcitabine is a frequently used chemotherapeutic agent which can be used as a monotherapy or in combination. However, tumors often develop resistance to gemcitabine. Previous studies show that the proto-oncogene PIM kinases (PIM1 and PIM3) are upregulated in PDAC compared to matched normal tissue and are related to chemoresistance and PDAC cell growth. The PIM kinases are also involved in the PI3K/AKT/mTOR pathway to promote cell survival. In this study, we evaluate the effect of the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, and commercially available PIM inhibitor, TP-3654. Using five human PDAC cell lines, we found AUM302 to be a potent inhibitor of cell proliferation, cell viability, cell cycle progression, and phosphoprotein expression, while TP-3654 was less effective. Significantly, AUM302 had a strong impact on the viability of gemcitabine-resistant PDAC cells. Taken together, these results demonstrate that AUM302 exhibits antitumor activity in human PDAC cells and thus has the potential to be an effective drug for PDAC therapy.