A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response-Dependent Survival of
Veronica Calvo1,2, Wei Zheng3,4,5, Anna Adam-Artigues3,4,5
1HiberCell, Inc., New York, New York.
Purpose:
The integrated stress response (ISR) kinase PERK serves as a survival factor for both proliferative and dormant cancer cells. We aim to validate PERK inhibition as a new strategy to specifically eliminate solitary disseminated cancer cells (DCC) in secondary sites that eventually reawake and originate metastasis.
Experimental Design:
A novel clinical-grade PERK inhibitor (HC4) was tested in mouse syngeneic and PDX models that present quiescent/dormant DCCs or growth-arrested cancer cells in micro-metastatic lesions that upregulate ISR.
Results:
HC4 significantly blocks metastasis, by killing quiescent/slow-cycling ISRhigh, but not proliferative ISRlow DCCs. HC4 blocked expansion of established micro-metastasis that contained ISRhigh slow-cycling cells. Single-cell gene expression profiling and imaging revealed that a significant proportion of solitary DCCs in lungs were indeed dormant and displayed an unresolved ER stress as revealed by high expression of a PERK-regulated signature. In human breast cancer metastasis biopsies, GADD34 expression (PERK-regulated gene) and quiescence were positively correlated. HC4 effectively eradicated dormant bone marrow DCCs, which usually persist after rounds of therapies. Importantly, treatment with CDK4/6 inhibitors (to force a quiescent state) followed by HC4 further reduced metastatic burden. In HNSCC and HER2+ cancers HC4 caused cell death in dormant DCCs. In HER2+ tumors, PERK inhibition caused killing by reducing HER2 activity because of sub-optimal HER2 trafficking and phosphorylation in response to EGF.
Conclusions:
Our data identify PERK as a unique vulnerability in quiescent or slow-cycling ISRhigh DCCs. The use of PERK inhibitors may allow targeting of pre-existing or therapy-induced growth arrested "persister" cells that escape anti-proliferative therapies.
Insights
Targeting the integrated stress response (ISR) kinase PERK with inhibitor HC4 effectively eliminates dormant cancer cells (DCCs) that cause metastasis. This strategy offers a new approach to eradicate therapy-resistant "persister" cells.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- The integrated stress response (ISR) kinase PERK is crucial for cancer cell survival, including dormant disseminated cancer cells (DCCs).
- DCCs are a major cause of metastasis and often survive conventional therapies, leading to disease recurrence.
- Targeting PERK presents a potential strategy to eliminate these resilient cancer populations.
Purpose of the Study:
- To validate PERK inhibition as a novel therapeutic strategy for eliminating solitary DCCs.
- To assess the efficacy of a novel clinical-grade PERK inhibitor (HC4) in preclinical cancer models.
- To investigate the role of PERK in the survival and dormancy of disseminated cancer cells.
Main Methods:
- Utilized mouse syngeneic and patient-derived xenograft (PDX) models with quiescent/dormant DCCs.
- Administered a novel clinical-grade PERK inhibitor (HC4).
- Employed single-cell gene expression profiling, imaging, and analysis of human metastasis biopsies.
Main Results:
- HC4 selectively killed quiescent/slow-cycling ISRhigh DCCs, but not proliferative ISRlow DCCs, significantly blocking metastasis.
- HC4 eradicated dormant DCCs in bone marrow and micro-metastases, including those in lung and head and neck squamous cell carcinoma (HNSCC) and HER2+ cancers.
- Combined treatment with CDK4/6 inhibitors and HC4 further reduced metastatic burden, demonstrating synergistic effects.
Conclusions:
- PERK is a unique vulnerability in quiescent/slow-cycling ISRhigh DCCs, offering a specific therapeutic target.
- PERK inhibitors like HC4 can target therapy-resistant "persister" cells that escape conventional anti-proliferative treatments.
- This approach may overcome treatment resistance and prevent metastatic relapse.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:34Inhibition of Cdk Activity
01:31The Intrinsic Apoptotic Pathway
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:38Mitogens and the Cell Cycle
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...