Combined xCT and mTOR Inhibition as a New Therapeutic Option for Pancreatic Adenocarcinoma

Abstract

Introduction: ACXT-3102 is an orally available cancer therapeutic that selectively targets the xCT transporter in tumor cells without causing significant toxicity. Inactivation of xCT results in oxidative stress and cell death, recently identified as ferroptosis. Furthermore, mTOR has been shown to modulate the xCT pathway. Therefore, we hypothesized that combination of xCT with an mTOR inhibitor would result in improved antitumor effects. Methods: Human and murine pancreatic cancer cell lines were treated in vitro with monotherapy (ACXT-3102 or the mTOR inhibitor Torin 1) or combination therapy for 48h. Cell viability was assessed by flow cytometry using a dye exclusion assay (7-AAD). C57BL/6 mice were implanted subcutaneously with syngeneic pancreatic cancer cells derived from the KPC tumor model. Athymic nude mice were implanted with human pancreatic cancer lines. All mice were treated for 14 days with ACXT-3102, Torin 1, ACXT-3102 + Torin 1 combination, or vehicle as a control. Results: The combination of ACXT-3102 and Torin 1 induced significantly more cell death in vitro than either compound alone (Fig. 1, p = 0.014, 0.0096). Also, combination treatment demonstrated significant tumor control in vivo (p < 0.05, data not shown). Conclusion: The enhanced therapeutic effect of a combined xCT (ACXT-3102) and mTOR inhibition (Torin 1) has been observed in vitro and in mouse models of PDAC. These results warrant additional evaluation as a novel therapy concept for PDAC patients.