Related Experiment Video
Updated: Sep 9, 2025
Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas
Published on: September 13, 2019
In vivo manipulation of the protein homeostasis network in rhabdomyosarcoma
Kristen Kwong1, Yue Pan1, Jacqueline Morales1
1Department of Pediatrics, Division of Oncology, University of California San Francisco, San Francisco, CA 94143, USA.
Abstract:
The protein homeostasis (proteostasis) network includes quality control systems that coordinate protein synthesis, folding, localization, and degradation, and is deregulated in numerous diseases including cancer. Loss of proteostasis can activate lethal cellular stress responses, potentially opening a therapeutic window. Previous research demonstrated that MAL3-101, an inhibitor of heat shock protein 70-kD (HSP70) chaperones, selectively induces rhabdomyosarcoma (RMS) cell death via unfolded protein response (UPR) activation. RMS is the most common pediatric soft tissue sarcoma, and relapsed patients are rarely cured despite transient responses to DNA-damaging therapy. To examine whether MAL3-101 or more drug-like proteostasis inhibitors represent a new therapeutic strategy for RMS, we screened proteostasis components that might recapitulate the effects of MAL3-101 in vivo. We find that inhibition of VCP, which encodes the p97 ATPase that facilitates proteasome-dependent degradation, similarly activates the UPR and induces RMS apoptosis. In mouse models, a preclinical p97 inhibitor showed superior bioavailability and anti-tumor activity compared to MAL3-101. Patient-derived xenografts exhibited a spectrum of p97 inhibitor sensitivities, and RNA sequencing of resistant tumors revealed elevated autophagy, nominating a biomarker of proteostasis adaptability. Together, these findings confirm that proteostasis inhibition can slow RMS growth and suggest that targeting compensatory network components might yield synergistic outcomes.
Insights
Targeting protein homeostasis (proteostasis) with p97 inhibitors shows promise for rhabdomyosarcoma (RMS) treatment. This approach activates the unfolded protein response (UPR) and induces cancer cell death, offering a new therapeutic strategy.
Area of Science:
- Molecular Biology
- Cancer Biology
- Drug Discovery
Background:
- The protein homeostasis (proteostasis) network is crucial for cellular health and is often dysregulated in cancer.
- Rhabdomyosarcoma (RMS), a pediatric soft tissue sarcoma, has limited treatment options for relapsed patients.
- Inhibiting heat shock protein 70-kD (HSP70) chaperones with MAL3-101 induces RMS cell death via unfolded protein response (UPR) activation.
Purpose of the Study:
- To investigate proteostasis inhibitors as a therapeutic strategy for RMS.
- To screen proteostasis components that could mimic MAL3-101's effects in vivo.
- To explore the therapeutic potential of targeting VCP (p97 ATPase) in RMS.
Main Methods:
- Screening of proteostasis components.
- Inhibition of VCP (p97 ATPase) and assessment of UPR activation and apoptosis in RMS cells.
- Evaluation of a preclinical p97 inhibitor in mouse models and patient-derived xenografts.
- RNA sequencing of resistant tumors to identify biomarkers.
Main Results:
- VCP inhibition activates the UPR and induces RMS apoptosis, similar to MAL3-101.
- A preclinical p97 inhibitor demonstrated improved bioavailability and anti-tumor activity compared to MAL3-101 in vivo.
- Tumor xenografts showed variable sensitivity to p97 inhibitors, with resistance linked to elevated autophagy.
Conclusions:
- Proteostasis inhibition, particularly targeting VCP, represents a viable therapeutic strategy for slowing RMS growth.
- Elevated autophagy in resistant tumors suggests it as a biomarker for proteostasis adaptability.
- Targeting compensatory mechanisms within the proteostasis network may lead to synergistic therapeutic outcomes in RMS.
Related Concept Videos
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:23Abnormal Proliferation