An α-specific PI3K inhibitor improves chemotherapy efficacy by inhibiting hepatic stellate cell activation in liver cancer

BACKGROUND AND AIMS: The poor response to current systemic treatments in liver cancer has been associated with the activation of cancer-associated fibroblasts (CAFs). Herein, we aimed to investigate the effects of chemotherapy on hepatic stellate cells (HSCs), the main origin of CAFs in liver cancer, and regulate HSC activation to improve treatment efficacy. APPROACH AND RESULTS: CAF subpopulations and alpha-smooth muscle actin expression were analyzed using a single-cell RNA sequencing dataset and immunohistochemical staining in patients. Alpha-smooth muscle actin expression was significantly increased as the proportion of CAFs enriched by COL1A1+ and ACTA2+ subpopulations in patients after transarterial chemoembolisation. In vitro experiments demonstrated that cisplatin activated HSCs through a paracrine effect of excessive reactive oxygen species (ROS) generated from tumor cells of hepatocellular carcinoma (HCC) and biliary tract cancer origin. RNA sequencing revealed that the PI3K signaling pathway underlined the activation of HSCs in response to excessive ROS. This was further analyzed in HCC mouse models on nonfibrotic and fibrotic livers. A 12-parameter flow cytometry panel validated a significant increase in activated CAF subsets in tumors following cisplatin treatment. Alpelisib, an α-specific PI3K inhibitor, selectively targeted PI3K p110α and completely inhibited HSC activation induced by cisplatin. A marked decrease in fibrosis areas was achieved along with a significant reduction of tumor burden in murine HCC models. CONCLUSIONS: This study demonstrates the role of platinum-based chemotherapy in HSC activation in liver cancer. Selective targeting of PI3K p110α may provide a novel strategy to inhibit chemotherapy-induced HSC activation and improve treatment response.