Data from A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response–Dependent Survival of Quiescent Cancer Cells

Abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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.</p>Results:<p>HC4 significantly blocks metastasis, by killing quiescent/slow-cycling ISR<sup>high</sup>, but not proliferative ISR<sup>low</sup> DCCs. HC4 blocked expansion of established micro-metastasis that contained ISR<sup>high</sup> slow-cycling cells. <i>S</i>ingle-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<sup>+</sup> cancers HC4 caused cell death in dormant DCCs. In HER2<sup>+</sup> tumors, PERK inhibition caused killing by reducing HER2 activity because of sub-optimal HER2 trafficking and phosphorylation in response to EGF.</p>Conclusions:<p>Our data identify PERK as a unique vulnerability in quiescent or slow-cycling ISR<sup>high</sup> DCCs. The use of PERK inhibitors may allow targeting of pre-existing or therapy-induced growth arrested “persister” cells that escape anti-proliferative therapies.</p></div>