PERK inhibition blocks metastasis initiation by limiting UPR-dependent survival of dormant disseminated cancer cells

Veronica Calvo, Wei Zheng, Kirk A. Staschke, Julie Cheung, Ana Rita Nobre, Eduardo F. Farias, Ari Nowacek, Mark Mulvihill, Alan C. Rigby, Julio A. Aguirre-Ghiso
2021 · doi:10.1101/2021.07.30.454473
preprint OA: closed
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In a mouse model of HER2-driven breast cancer, PERK inhibition blocked metastasis by eliminating dormant disseminated cancer cells that relied on the unfolded protein response for survival, while also altering primary tumor HER2 activity.

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Abstract

The unfolded protein response (UPR) kinase PERK has been shown to serve as a survival factor for HER2-driven breast and prostate cancers as well as for dormant cancer cells. However, its role in metastasis is not understood. Here we found in the MMTV-HER2 mouse model that quiescent HER2+ disseminated cancer cells (DCCs) displayed unresolved ER stress as revealed by high expression of the PERK-inducible GADD34 gene. S ingle cell gene expression profiling and imaging confirmed that a significant proportion of DCCs in lungs were dormant and displayed an active UPR. In human breast cancer metastasis biopsies, GADD34 expression and quiescence were also positively correlated. Importantly, PERK inhibition with a specific inhibitor (HC4) blunted metastasis development by selectively killing UPR high quiescent but not proliferative DCCs. We also show that PERK inhibition altered optimal HER2 activity in primary tumors as a result of sub-optimal HER2 trafficking and phosphorylation in response to EGF. Our data identify PERK as a unique “Achilles heel” in dormant DTCs, supporting a requisite role for PERK in DTCs. Taken together, these data identify novel strategies to eliminate quiescent DCCs in patients with disseminated cancer disease.

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