Related Experiment Video
Updated: Jun 2, 2026
The Use of Reverse Phase Protein Arrays (RPPA) to Explore Protein Expression Variation within Individual Renal Cell Cancers
Published on: January 22, 2013
Resistance of renal cell carcinoma to sorafenib is mediated by potentially reversible gene expression
Liang Zhang1, Manoj Bhasin, Rachel Schor-Bardach
1Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
Purpose:
Resistance to antiangiogenic therapy is an important clinical problem. We examined whether resistance occurs at least in part via reversible, physiologic changes in the tumor, or results solely from stable genetic changes in resistant tumor cells.
Experimental Design:
Mice bearing two human RCC xenografts were treated with sorafenib until they acquired resistance. Resistant 786-O cells were harvested and reimplanted into naïve mice. Mice bearing resistant A498 cells were subjected to a 1 week treatment break. Sorafenib was then again administered to both sets of mice. Tumor growth patterns, gene expression, viability, blood vessel density, and perfusion were serially assessed in treated vs control mice.
Results:
Despite prior resistance, reimplanted 786-O tumors maintained their ability to stabilize on sorafenib in sequential reimplantation steps. A transcriptome profile of the tumors revealed that the gene expression profile of tumors upon reimplantation reapproximated that of the untreated tumors and was distinct from tumors exhibiting resistance to sorafenib. In A498 tumors, revascularization was noted with resistance and cessation of sorafenib therapy and tumor perfusion was reduced and tumor cell necrosis enhanced with re-exposure to sorafenib.
Conclusions:
In two RCC cell lines, resistance to sorafenib appears to be reversible. These results support the hypothesis that resistance to VEGF pathway therapy is not solely the result of a permanent genetic change in the tumor or selection of resistant clones, but rather is due to a great extent to reversible changes that likely occur in the tumor and/or its microenvironment.
Insights
Resistance to antiangiogenic therapy, like sorafenib, in renal cell carcinoma (RCC) appears reversible. Tumor resistance may stem from temporary physiologic changes rather than permanent genetic mutations, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Antiangiogenic therapies, such as sorafenib, are crucial in treating renal cell carcinoma (RCC).
- Acquired resistance to these therapies poses a significant clinical challenge, limiting treatment efficacy.
- Understanding the mechanisms of resistance is vital for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate whether resistance to sorafenib in RCC is due to reversible physiologic changes or stable genetic alterations.
- To determine if resistance mechanisms can be overcome by altering treatment or tumor microenvironment.
Main Methods:
- Mice with human RCC xenografts (786-O and A498) were treated with sorafenib until resistance developed.
- Resistant cells were reimplanted, or treatment was interrupted, followed by re-challenge with sorafenib.
- Tumor growth, gene expression, vascularization, and perfusion were assessed.
Main Results:
- Reimplanted 786-O tumors regained sensitivity to sorafenib, with gene expression profiles returning to pre-resistance states.
- A498 tumors showed revascularization upon resistance; sorafenib re-exposure reduced perfusion and increased necrosis.
- These findings suggest resistance is not solely due to genetic mutations.
Conclusions:
- Resistance to sorafenib in RCC xenografts appears to be reversible.
- The study supports the hypothesis that reversible tumor and/or microenvironment changes contribute significantly to resistance.
- This reversibility suggests potential for overcoming resistance through therapeutic modulation.
More Related Videos
08:59Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
Published on: December 11, 2017
09:38Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Related Concept Videos
02:56Treatment Resistant Cancers
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...