Concurrent inhibition of JAK2 and FLT3 by pacritinib is a promising therapeutic strategy for hepatocellular carcinoma

Abstract Background Hepatocellular carcinoma (HCC) remains a major therapeutic challenge due to the limited efficacy of current systemic therapies with substantial intra-tumoral heterogeneity. The modest clinical benefit of multi-kinase inhibitors such as sorafenib underscores the need for alternative multi-kinase therapeutic strategies. Here, we investigated the therapeutic potential of concurrent JAK2 and FLT3 inhibition by pacritinib in HCC. Methods The antitumor effects of pacritinib were evaluated in HCC cell lines, HCC organoids, and an organoid-derived xenograft model, with sorafenib used as a comparator. Single-cell RNA sequencing was performed in a representative HCC organoid to characterize treatment responses across transcriptionally distinct tumor cell populations. Results Concurrent inhibition of JAK2 and FLT3 by pacritinib potently suppressed HCC cell growth, accompanied by inhibition of JAK2/STAT3 and FLT3 signaling, and showed greater antitumor activity than sorafenib in both HCC cell lines and organoids. Marked tumor growth inhibition was also observed in an organoid-derived xenograft model. Single-cell RNA sequencing of a representative HCC organoid revealed consistent responses across three transcriptionally distinct tumor cell populations, with suppression of cell-cycle progression and DNA replication programs. Conclusions These findings support the therapeutic potential of pacritinib in HCC and suggest that concurrent inhibition of JAK2 and FLT3 may represent a promising strategy for molecularly heterogeneous HCC.