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Updated: May 8, 2026
A Hepatocellular Cancer Patient-Derived Organoid Xenograft Model to Investigate Impact of Liver Regeneration on Tumor Growth
Published on: February 2, 2024
Reversibility of regorafenib effects in hepatocellular carcinoma cells
Purpose:
Multikinase growth inhibitors inhibit their target kinases with varying potency. Patients often require lower doses or therapy breaks due to drug toxicities. To evaluate the effects of drug withdrawal on hepatocellular carcinoma cells after incubation with growth-inhibitory concentrations of regorafenib, cell growth, migration and invasion, and signaling were examined.
Methods:
Cell proliferation, motility, and invasion were analyzed by MTT, wound healing, and invasion assays, respectively, and MAPK pathway protein markers were analyzed by Western blot.
Results:
After regorafenib removal, cell growth, migration, and invasion recovered. Repeated drug exposure resulted in changes in cell growth patterns. Recovery could be blocked by sub-growth-inhibitory concentrations of either doxorubicin or vitamin K1. Recovery of growth was associated with increased phospho-JNK, phospho-p38, and phospho-STAT3 levels. The recovery of growth, migration, and signaling were blocked by a JNK inhibitor.
Conclusions:
Removal of regorafenib from growth-inhibited cells resulted in a JNK-dependent recovery of growth and migration.
Insights
Regorafenib withdrawal in hepatocellular carcinoma cells led to recovery of growth and migration. This recovery was dependent on JNK signaling and could be blocked by specific inhibitors, suggesting therapeutic implications.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multikinase inhibitors like regorafenib are used in cancer therapy but often require dose adjustments due to toxicity.
- Understanding cellular responses to drug withdrawal is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the effects of regorafenib withdrawal on hepatocellular carcinoma (HCC) cell growth, migration, invasion, and signaling pathways.
- To determine the mechanisms underlying cellular recovery after regorafenib discontinuation.
Main Methods:
- Cell proliferation, migration, and invasion were assessed using MTT, wound healing, and invasion assays.
- Mitogen-activated protein kinase (MAPK) pathway signaling was analyzed via Western blot.
- The impact of doxorubicin, vitamin K1, and a JNK inhibitor on cell recovery was evaluated.
Main Results:
- Regorafenib removal resulted in the recovery of HCC cell growth, migration, and invasion.
- Repeated drug exposure altered cell growth patterns.
- Recovery was associated with increased levels of phospho-JNK, phospho-p38, and phospho-STAT3.
- A JNK inhibitor effectively blocked the recovery of growth, migration, and signaling.
Conclusions:
- Regorafenib withdrawal triggers a JNK-dependent recovery of growth and migration in HCC cells.
- These findings highlight the role of JNK signaling in mediating resistance or recovery after kinase inhibitor treatment.
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