Fig. 8: Filgotinib or MRX-2843 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo.
From: Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma
a–f Representative heatmaps for cell viability using MHH-ES-1 (a, b, c, e) or TC-71 cells (d, f) treated with indicated doses of compounds for 2 days. g Tumor volume measurements at indicated days post-injection of MHH-ES-1 cells subcutaneously with indicated compounds (irinotecan (10 mg/kg) and filgotinib (10 mg/kg)) injected by IP. Error bars were calculated as mean ± SD, n = 5 tumors. p values are calculated by two-way ANOVA followed by the Tukey multiple comparison test. h Isolated tumors from (g) and weighed in (i). Error bars were calculated as mean ± SD, n = 5 tumors. p values are calculated by a two-tailed student’s t-test. j, k Representative heatmaps for cell viability in MHH-ES-1 cells treated with indicated doses of compounds for 2 days. l Tumor volume measurements at indicated days post-injection of MHH-ES-1 cells with indicated compounds IP injected or by oral gavage at the indicated days. Error bars were calculated as mean ± SD, n = 5 tumors. p values are calculated as indicated (two-way ANOVA followed by Tukey multiple comparison test). m Isolated tumors from (l) and weighed in (n). Error bars were calculated as mean ± SD, n = 5 tumors. p values are calculated as indicated (two-tailed student’s t- test). o Animal body weight measurements at indicated days. Error bars were calculated as mean ± SD, n = 5 animals in each group. p A cartoon illustration for a proposed model. Chemotherapy triggers DNA damage and activates DNA-damaging kinases to phosphorylate the JAK1-S571Q motif leading to JAK1 activation and subsequent STAT6-Y641 phosphorylation. This causes STAT6 nuclear translocation to promote GAS6 transcription and secretion that binds and activates TAM kinases via either autocrine or paracrine manners, which further activates Akt and ERK signaling contributing to chemoresistance. Blocking either JAK1 by filgotinib or TAM kinases by clinical inhibitor MRX-2843 sensitizes Ewing sarcoma to conventional chemotherapy.
