Ciclesonide May Ease Sorafenib Resistance in Liver Cancer, Study Suggests

A new study published in BMC Cancer reports a strategy to tackle this problem by combining a CRISPR activation screen with large-scale genomic data from the TCGA, TARGET and GTEx datasets. The work, led by Tian Liu, Kewei Liu, Yongying Hou and colleagues, was shared early as a peer-reviewed, accepted research article carrying a permanent DOI, with the final version of record to follow.

The researchers first used the CRISPR activation screen to identify genes associated with sorafenib sensitivity. They then integrated these results with clinical and transcriptomic data and applied univariate Cox regression and LASSO regression to build a five-gene prognostic signature. The genes involved are AKR1B15, BMF, GBA, GINS2 and SMC2. According to the abstract, this signature classifies patients by their likely overall survival and their probable response to sorafenib, offering a way to stratify liver cancer patients before treatment decisions are made.

In the TCGA-LIHC training cohort of 371 patients, those with high-risk scores calculated from the signature showed significantly worse overall survival and reduced sensitivity to sorafenib. The authors report that this pattern was validated in the ICGC-US cohort, an independent dataset. High risk scores also correlated with adverse clinicopathological features, meaning patients in the high-risk group tended to present with more aggressive disease characteristics. The team states that the signature functioned as an independent prognostic factor in their analyses.

These findings suggest that the five-gene signature could serve as a biomarker to help identify which hepatocellular carcinoma patients are unlikely to benefit from sorafenib alone.

To address the problem of patients who are insensitive to sorafenib, the researchers turned to drug perturbation Gene Set Enrichment Analysis, abbreviated dpGSEA. Through this analysis, ciclesonide, a drug not previously positioned as a cancer therapy in this context, emerged as a potential sensitizer to sorafenib.

The team then tested this prediction experimentally. According to the key points accompanying the article, both in vitro and in vivo experiments supported the combination strategy, indicating that the effect was not limited to a single experimental setting.

To probe the mechanism, the researchers performed RNA sequencing on treated samples. The analysis suggested that ciclesonide may act through regulation of the cell cycle pathway. In the authors’ formulation, the drug might be associated with downregulation of cell cycle-related transcriptional programs, and this suppression of cell cycle gene expression could contribute to the enhanced antitumor activity observed when ciclesonide is combined with sorafenib. The study presents this as a suggested mechanism rather than a definitively proven one, since RNA sequencing reveals transcriptional correlates rather than direct causal proof.

The authors conclude that the sorafenib drug sensitivity-related prognostic signature may serve as an independent prognostic biomarker and a predictor of sorafenib sensitivity in hepatocellular carcinoma, while the combination of sorafenib and ciclesonide represents a promising strategy to improve targeted therapy. They frame the work as a step toward personalized treatment selection, in which molecular stratification identifies patients who need an adjuvant agent and points to a specific candidate drug for that purpose.

Several caveats apply. The clinical stratification rests on retrospective cohort analyses, and the drug combination findings come from cell culture and xenograft models rather than human trials. The article was also released in a pre-publication form that is subject to further edits before the final version of record appears.

Subject of Research: A CRISPR activation screen combined with TCGA and ICGC data identifies a five-gene prognostic signature for sorafenib sensitivity in hepatocellular carcinoma and points to ciclesonide as a potential adjuvant drug.

Article Title: CRISPR screening-informed liver cancer stratification identifies ciclesonide as a novel adjuvant drug to alleviate sorafenib resistance

Article References: Liu, T., Liu, K., Hou, Y., Chu, Z., Li, J., Sun, M., Wu, L., Liu, Q., Zhou, Z., Zhang, Q., Wang, B., Wen, Q., Wang, X., & Min, J. (2026). CRISPR screening-informed liver cancer stratification identifies ciclesonide as a novel adjuvant drug to alleviate sorafenib resistance. BMC Cancer. https://doi.org/10.1186/s12885-026-17205-6

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17205-6

Keywords: hepatocellular carcinoma, sorafenib resistance, CRISPR activation screen, prognostic signature, ciclesonide, drug repurposing, TCGA, ICGC, RNA sequencing, cell cycle pathway, xenograft model, BMC Cancer