Related Experiment Video
Updated: Jul 16, 2025
Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors
Michael E Stokes1, Veronica Calvo1, Sho Fujisawa1
1HiberCell, Inc., New York City, New York.
Purpose:
Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI).
Experimental Design:
HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.
Results:
VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group.
Conclusions:
By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.
Insights
Inhibiting the PERK stress response with HC-5404 significantly enhances the effectiveness of VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI) in treating renal cell carcinoma (RCC) models, leading to tumor regression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Tumors utilize the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) pathway as a survival mechanism against stress like hypoxia.
- VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI) are standard treatments for renal cell carcinoma (RCC).
- PERK activation is observed in response to VEGFR-TKI treatment in RCC models.
Purpose of the Study:
- To investigate if inhibiting PERK with a novel compound, HC-5404, can improve the antitumor efficacy of VEGFR-TKI.
- To evaluate the combination therapy of HC-5404 and VEGFR-TKI in preclinical RCC models.
Main Methods:
- HC-5404 was characterized as a potent and selective PERK inhibitor with favorable in vivo properties.
- Multiple RCC tumor models were treated with HC-5404 in combination with various VEGFR-TKI (axitinib, cabozantinib, lenvatinib, sunitinib).
- Tumor volume, protein analysis, and immunohistochemistry (IHC) were used to assess treatment response.
Main Results:
- HC-5404 effectively inhibited PERK in tumors when combined with VEGFR-TKI.
- The combination therapy led to significant antitumor effects, including tumor stasis and regression, across multiple RCC models.
- HC-5404 enhanced the antiangiogenic activity of VEGFR-TKI by inhibiting both new and mature tumor vasculature.
- Even in models resistant to axitinib monotherapy, the combination achieved approximately 20% tumor regression.
- In patient-derived xenograft (PDX) models, the combination therapy demonstrated superior antitumor effects compared to monotherapies, with nine out of 18 models showing ≥50% regression.
Conclusions:
- Inhibiting the PERK adaptive stress response with HC-5404 can overcome resistance mechanisms.
- This combination strategy offers a promising clinical approach to enhance the efficacy of standard VEGFR-TKI therapies for RCC.
- HC-5404 represents a potential therapeutic agent to improve outcomes in renal cell carcinoma treatment.
More Related Videos
10:49Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
08:15Author Spotlight: Network Pharmacology and Molecular Docking to Decipher the Action of Jiawei Shengjiang San Against Diabetic Kidney Disease
Published on: May 10, 2024
Related Concept Videos
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
02:34Inhibition of Cdk Activity
01:27Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
01:25Antihypertensive Drugs: Direct Renin Inhibitors
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...