BCN057, a Modulator of GSK3β, Induces KRAS G12D Mutant Pancreatic Cancer Cell Death

Abstract

Effective treatment for Pancreatic Cancer remains a major challenge due to its resistance to radiation/chemotherapy and poor drug permeability. Moreover, treatment induced normal tissue toxicity, mainly to the duodenum and gastrointestinal epithelium, is common and is a dose limiting event, while toxicity to the pancreas is relatively rare. Gastrointestinal toxicity, however, often results in interruption, reduction or premature withdrawal of anti–cancer therapy which is a very significant factor impacting the overall survival of patients being treated. Therefore, development of a therapeutic strategy to selectively sensitize tumor tissue without inducing normal tissue toxicity is important. In this manuscript, we show that the novel small molecule BCN057 can modulate chemo–sensitivity of oncogenic RAS pancreatic cancer cells while conversely protecting normal intestinal epithelium from off target toxicity. In particular, BCN 057 protects Lgr5 positive intestinal stem cells, thereby preserving barrier function. Further, it is demonstrated that BCN057 inhibits GSK3β and thereby induces a pro apoptotic phosphorylation pattern on c–Jun in KRAS G12D mutant pancreatic cancer cells (Panc1) leading to the restoration of PTEN expression and consequent apoptosis. This appears to be a new mechanistic observation for the oncogenic RAS phenotype. Lastly, concurrent with its GSK3β inhibition, BCN057 is a small molecule inhibitor of PD–1 expression on human T–lymphocytes co cultured with human pancreatic cancer cells. In summary, BCN057 can promote synthetic lethality specifically to malignant cells and therefore should be considered to improve the therapeutic ratio in pancreatic and epithelial cancer treatment in conjunction with chemotherapy and radiation.