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Supplementary Figure S3 from A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response–Dependent Survival of Quiescent Cancer Cells

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posted on 2023-12-15, 08:40 authored by Veronica Calvo, Wei Zheng, Anna Adam-Artigues, Kirk A. Staschke, Xin Huang, Julie F. Cheung, Ana Rita Nobre, Sho Fujisawa, David Liu, Maria Fumagalli, David Surguladze, Michael E. Stokes, Ari Nowacek, Mark Mulvihill, Eduardo F. Farias, Julio A. Aguirre-Ghiso

Supplementary Figure S3. (a) Representative images of carmine staining of whole mount FVB normal mammary gland compared to vehicle- andHC4-treated MMTV-HER2 mammary gland whole mount. Scale bar 2 mm.(b) Examples of the mammary gland histological structures quantified.Scale bar 3 mm. Number of normal branches in the mammary gland ductal tree of non-tumor bearing healthy mice treated with vehicle (N=14) orHC4 (N=10). P by Mann-Whitney test. (c) The panels show representative images of histological sections showing at low magnification (top row 100µm scale bar) the indicated ductal and early lesion structures; the lower row showed higher magnification (25 µm scale bars) these structures. Theseimages were used as a key to classify per animal the effects of control or HC4 treatments.

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Ramon Areces Foundation

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Congressionally Directed Medical Research Programs (CDMRP)

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ARTICLE ABSTRACT

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. 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. 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. 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.

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