Today, pancreatic cancer (PC) is a major health problem in the United States. It remains a challenge to develop efficacious clinically useful PC therapies. New avenues, based on translational approaches and innovative validated biomarkers could be a preclinical option to evaluate PC drug candidates or drug combinations before clinical trials. Herein, we describe evaluation of combination therapies by incorporating a novel pathway modulator, p53-Activator Wnt Inhibitor-2 (PAWI-2) with other FDA-approved cancer drugs that have been used in PC clinical trials. PAWI-2 is a potent inhibitor of drug-resistant PC cells that has been shown to selectively ameliorate human pancreatic cancer stem cells (i.e., hPCSCs, FGβ3 cells). In the present study, we showed PAWI-2 produced therapeutic synergism with certain types of anti-cancer drugs. These drugs themselves oftentimes do not ameliorate PC cells (especially PCSCs) due to high levels of drug-resistance. PAWI-2 has the ability to rescue the potency of drugs (i.e., erlotinib, trametinib) and inhibit PC cell growth. Key molecular regulators of PAWI-2 could be used to predict synergistic/antagonistic effects between PAWI-2 and other anti-cancer drugs. Anti-cancer results showed potency could be quite accurately correlated to phosphorylation of optineurin (OPTN) in PC cells. Synergism/antagonism was also associated with inhibition of PCSC marker SOX2 that was observed in FGβ3 cells. Synergism broadens the potential use of PAWI-2 as an adjunct chemotherapy in patients with PC that have developed resistance to first-line targeted therapies or chemotherapies.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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We thank Dr. Andrew Lowy of the University of California, San Diego for 779E cells. We also thank Dr. David Cheresh of the University of California, San Diego and The Scripps Research Institute for FG and FGβ3 cells. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of CIRM or any other agency of the State of California.
This work was supported by an Inception Award from the California Institute for Regenerative Medicine (CIRM) (DISC1–10583; J. R. Cashman) and by funds from the Human BioMolecular Research Institute and ChemRegen, Inc. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of CIRM or any other agency of the State of California.
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Cheng, J., Cashman, J.R. Pancreatic cancer drug-sensitivity predicted by synergy of p53-Activator Wnt Inhibitor-2 (PAWI-2) and protein biomarker expression. Invest New Drugs 39, 131–141 (2021). https://doi.org/10.1007/s10637-020-00998-z
- Pancreatic cancer cells
- Cancer stemness
- Drug resistance
- Drug sensitivity
- Drug synergy
- Cell cycle arrest