PAWI‐2 Overcomes Tumor Stemness and Drug Resistance in Pancreatic Cancer Stem Cells

Abstract

Today, pancreatic cancer (PC) remains a major health problem in the US and soon will be the second most common cause of mortality due to cancer. However, most of the front‐line PC chemotherapies cause serious side effects and a majority of patients with PC are often resistant to clinical therapies. The fact that cancer stem cells (CSCs) become enriched after anti‐cancer therapy implicates CSCs as key contributors to tumor dormancy, metastasis, and relapse in PC. Given the important role of human pancreatic cancer stem cells (hPCSCs) in PC, development of a novel treatment strategy that targets hPCSCs or their extrinsic and intrinsic regulators could be of great clinical utility to treat PC. Herein, we used a highly validated hPCSCs model (FGβ3 cells) to test a novel compound (PAWI‐2) to target CSCs. In this hPCSC model, integrin αvβ3 expression was shown to be a marker/functional contributor to CSC progression and drug resistance attributed to its ability to trigger anchorage‐independent cell survival and tumor metastasis. Specifically, integrin αvβ3 recruits KRAS and RalB to tumor cell plasma membranes to activate NF‐κB signaling that triggers dysregulated KRAS‐RalB‐NF‐κB pathways. This was shown to be a pharmacological target to reverse CSC‐like properties or re‐sensitize drug resistance (e.g., EGFR inhibitors, erlotinib) of established FGβ3 tumors. Compared to parental FG cells, PAWI‐2 showed greater potency to inhibit cell viability and self‐renewal capacity of FGβ3 cells. PAWI‐2 inhibited dysregulated integrin β3‐KRAS‐RalB‐NF‐κB signaling independent of KRAS and Ral. This is clinically relevant because >90% of KRAS is activated by mutations in PC and RAS or Ral inhibitors have not proven effective clinically. PAWI‐2 targeted downstream of KRAS signaling and was negatively regulated by other feedback mechanisms. This was further shown by genetic knockdown of key regulator and co‐treatment of specific inhibitors. PAWI‐2 overcomes erlotinib resistance in FGβ3 cells with greater potency than bortezomib. In the proposed mechanism of PAWI‐2 action, key regulators link the inhibition of KRAS signaling and cell cycle arrest (G2/M). The great utility and pharmacological potency of PAWI‐2 in FGβ3 cells (that possess stem‐like properties) compared to FG cells provide a basis for further development. PAWI‐2 as an efficient therapeutic to reverse tumor stemness and resensitize CSC tumors to drug inhibition.Support or Funding InformationThis work was supported by Inception Award from California Institute for Regenerative Medicine (CIRM) (DISC1‐10583; J.R. Cashman) and by funds from the Human BioMolecular Research Institute.