Concurrent inhibition of JAK2 and FLT3 by pacritinib is a promising therapeutic strategy for hepatocellular carcinoma
This study demonstrates that pacritinib, a dual inhibitor of JAK2 and FLT3, exhibits superior antitumor activity against molecularly heterogeneous hepatocellular carcinoma compared to sorafenib by potently suppressing cell growth and key signaling pathways across diverse tumor cell populations.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer
Liver cancer, specifically a type called hepatocellular carcinoma, remains one of the most difficult diseases to treat. While doctors have developed drugs that can slow the disease down, they rarely stop it completely, and many patients eventually stop responding to these treatments. The liver is a complex organ, and the tumors that grow within it are often a chaotic mix of different cell types, making it hard to find a single target that works for everyone. For years, the standard approach has been to use broad-spectrum drugs that block many different pathways at once, hoping to hit the right one. However, this strategy often yields only modest results, leaving researchers searching for a more precise way to shut down the cancer's growth engines.
In a new study, scientists investigated a different approach by looking at two specific proteins that act as signals for cell growth: JAK2 and FLT3. Think of these proteins as switches on the surface of a cell that tell it when to divide and survive. In many cancers, these switches get stuck in the "on" position, causing cells to multiply uncontrollably. The researchers focused on a drug called pacritinib, which is already approved for use in other blood cancers. Unlike the broad-spectrum drugs currently used for liver cancer, pacritinib is designed to turn off both the JAK2 and FLT3 switches at the same time. The team wanted to see if this dual-action strategy could work better for liver cancer, especially in cases where the current standard treatments fail.
To test this, the researchers started by looking at human liver cancer cells grown in a lab. They confirmed that the JAK2 switch was often highly active in these cancer cells, while the FLT3 switch was present but sometimes less active. Despite the lower levels of FLT3, turning it off still slowed the cancer down. When the scientists treated the cells with pacritinib, they saw that the drug successfully turned off both switches. This action stopped the cells from dividing and caused them to die off. The drug worked across a wide variety of liver cancer cell lines, suggesting it could be effective against many different types of the disease.
The team then moved to a more realistic model to see how the drug would behave in a complex environment. Instead of simple flat cells, they grew three-dimensional clusters of liver cancer cells, known as organoids, which mimic the structure and diversity of a real tumor. They found that pacritinib was highly effective at shrinking these organoids. To understand exactly what was happening inside, the researchers used a powerful technique called single-cell RNA sequencing. This allowed them to look at the genetic activity of thousands of individual cells within a single tumor cluster. They discovered that the tumor was made up of three distinct groups of cells, each with slightly different genetic profiles. Crucially, pacritinib suppressed the growth signals in all three groups equally. There was no hidden group of cells that was naturally resistant to the drug; the treatment worked consistently across the entire tumor population.
The study also compared pacritinib directly to sorafenib, the most common drug currently used to treat advanced liver cancer. In head-to-head tests using both the simple cell lines and the complex organoids, pacritinib consistently outperformed sorafenib, stopping the cancer from growing more effectively. The researchers also looked at why sorafenib sometimes fails. They found that in patients who did not respond well to sorafenib, the FLT3 switch was often turned down, but the JAK2 switch was turned up. This suggested that when one target is weak, the cancer relies more heavily on the other. By blocking both simultaneously, pacritinib overcomes this weakness. When the scientists tried combining pacritinib with sorafenib, they found that adding sorafenib did not make the treatment any better than using pacritinib alone, indicating that the new drug is the stronger option on its own.
Finally, the researchers tested the drug in mice that had human liver tumors growing under their skin. The mice were given pacritinib daily, and the results mirrored what was seen in the lab. The tumors in the treated mice shrank significantly compared to those in the untreated group, and the mice did not lose weight, suggesting the drug was not causing severe side effects. Inside the tumors, the drug successfully blocked the JAK2 and FLT3 signals and triggered cell death. These findings suggest that targeting both JAK2 and FLT3 at the same time is a promising strategy for treating liver cancer, offering a potential alternative for patients who do not get enough benefit from current therapies. The study provides strong evidence that this dual approach could work even in tumors that are genetically diverse and resistant to other treatments.
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