Calvo, VeronicaZheng, WeiAdam-Artigues, AnnaStaschke, Kirk A.Huang, XinCheung, Julie F.Nobre, Ana RitaFujisawa, ShoLiu, DavidFumagalli, MariaSurguladze, DavidStokes, Michael E.Nowacek, AriMulvihill, MarkFarias, Eduardo F.Aguirre-Ghiso, Julio A.2024-09-092024-09-092023Calvo V, Zheng W, Adam-Artigues A, et al. A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response-Dependent Survival of Quiescent Cancer Cells. Clin Cancer Res. 2023;29(24):5155-5172. doi:10.1158/1078-0432.CCR-23-1427https://hdl.handle.net/1805/43200Purpose: 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.en-USPublisher PolicyBreast neoplasmsCell cycleCell deathCell proliferationeIF-2 kinaseArticle