Pancreatic cancer drug-sensitivity predicted by synergy of p53-Activator Wnt Inhibitor-2 (PAWI-2) and protein biomarker expression

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.