Fig. 7: Targeting CAFs increases anti-GIST therapeutic drug sensitivity in vivo.
a Antitumor efficacy of imatinib, gedatolisib, or both in combination. All tumor (top) and graphical representative IVIS images (bottom) are shown for all 4 groups 5 weeks after injection. T1-mCherry (5 × 106 cells) cells mixed with CAFs (1 × 106 cells) at a 5:1 ratio (n = 32) were subcutaneously injected into nude mice. After randomization (n = 8 per group), the mice were treated with imatinib (10 mg/kg), gedatolisib (10 mg/kg), or both in combination. Imatinib was administrated intraperitoneally (IP), and gedatolisib was administrated intravenously thrice weekly for 3 weeks. b Tumor burden quantification. Tumor growth over time as quantified by total photon flux (p/s) using IVIS. p values were represented by ANOVA analysis. ***p < 0.001. c Tumor weight of each group was measured after all tumors were harvested on day 35. p values were represented by ANOVA analysis. **p < 0.01, ***p < 0.001. d Representative IHC images stained for Ki67 (a cell proliferation marker; top) and cleaved caspase-3 (an apoptosis marker; bottom) in the tumor sections collected from each group. Scale bars, 50 µm. Quantification of IHC of Ki67 (e), p-Histone H3 (f), and cleaved caspase-3 (g) in the indicated drug-treated conditions. p values were represented by ANOVA analysis. *p < 0.05, **p < 0.01, ***p < 0.001. h A proposed model demonstrating how paracrine fibroblastic support drives GIST progression and metastasis (left), and how targeting CAFs enhances anti-GIST therapy (right).
