ESMO Congress 2023 | OncologyPRO

Abstract 2348P

Background

Esophageal squamous cell carcinoma is a malignance with high invasiveness. Cancer-associated fibroblasts (CAFs) as one major component of tumor microenvironment (TME), promotes tumor initiation and progression. Our previous studies revealed that CAFs mediated ESCC cells significant resistance to a variety of chemotherapeutic drugs and ionizing irradiation. How to inhibit the tumor-promoting activity of CAFs is of critically important for the radical treatment of ESCC.

Methods

Using high-throughput screening, 157 inhibitors of cytokines/chemokines were tested for their effect on the cell viability of CAFs, matched normal fibroblasts (NFs), ESCC cells as well as normal esophageal epithelial cell Het-1A. We also investigated the effect of the inhibitors on cell cycle distribution, ROS accumulation and cell apoptosis of CAFs. The expressions of α-SMA, a marker of CAFs activation, was detected in CAFs treated with the inhibitors. By establishment of xenograft tumors in BALB/c mice, the effect of the inhibitors on CAFs-promoted ESCC growth was studied.

Results

By high-throughput screening, GSK1838705A, an inhibitor of IGF-1R kinase, was discovered as a potent inhibitor of CAFs activity in ESCC. Compared with NFs, ESCC cells as well as Het-1A, the viability of CAFs was significantly reduced when exposure to GSK1838705A. Furthermore, GSK1838705A arrested the cell cycle of CAFs in G2/M phase, promoted cell apoptosis and ROS accumulation. The expression of α-SMA was signifcantly reduced when CAFs were treated with GSK1838705A. In vivo studies demonstrated that GSK1838705A significantly repressed the tumor-promoting activity of CAFs. Immunohistochemical analysis showed that GSK1838705A significantly reduced the percentage of CAFs in xenograft tumor tissues.

Conclusions

GSK1838705A is a potent inhibitor of CAFs which promote ESCC progression. The combination of GSK1838705A and chemoradiotherapy may be a promising strategy against ESCC.