Tumor stiffness as an imaging biomarker of tyrosine kinase inhibitor response: A preclinical study.

[OBJECTIVE] Tyrosine kinase inhibitors (TKIs), such as sorafenib, are standard therapies for advanced hepatocellular carcinoma (HCC), but their biomechanical impact and the role of magnetic resonance elastography (MRE) in treatment evaluation remain unclear. This study explored whether TKIs reduce tumor stiffness by inhibiting malignant behavior and whether MRE can detect such changes early.

[METHODS] A prospective animal study was performed using subcutaneous SK-HEP-1 HCC xenografts in 50 nude rats. Forty tumor-bearing rats were randomized to control or sorafenib-treated groups (n = 20 each). Multiparametric 3.0 T MRI included T1- and T2-weighted imaging, T1/T2/T2* mapping, and MRE at 200 Hz and 100 Hz. Imaging was conducted at baseline (∼2 cm tumor volume) and on days 1, 2, and 3 post-intervention. Histology involved H&E and immunohistochemistry for VEGFR-1, BRAF, Ki67, and TUNEL. Ex vivo stiffness was measured by atomic force microscopy. Cell behavior was assessed by EdU, Transwell, CCK-8, and Western blot. Statistical analysis included ICC, Bland-Altman, Mann-Whitney U, repeated measures ANOVA, Spearman correlation, and multivariate regression.

[RESULTS] TKIs reduced tumor stiffness at cellular (P = 0.02) and tissue (P = 0.004) levels. Stiffness decreased by day 2 at 200 Hz and day 3 at both frequencies. Treated tumors showed reduced cellularity, lower Ki67, and increased apoptosis. Stiffness correlated with cellularity (r = 0.527) and Ki67 (r = 0.623), both predicting MRE stiffness (R = 0.537).

[CONCLUSION] TKIs reduce stiffness and malignancy in HCC. MRE is a promising tool for early treatment response evaluation.