A Perk Inhibitor That Blocks Her2-Driven Tumorigenesis And Suppresses Metastasis By Targeting Single Disseminated Tumor Cells

The unfolded protein response (UPR) is a critical survival and adaptation pathway in cancer cells. The endoplasmic reticulum kinase PERK serves as a survival UPR factor for different tumor types, including those driven by the oncogene HER2, and it can also promote survival of dormant cancer cells. We wanted to evaluate the effect of a potent and selective new PERK inhibitor (LY4) on MMTV-HER2-driven tumorigenesis that, through genetic experiments, was shown to depend on a full complement of PERK for progression. Here we show that, from ductal carcinoma in situ (DCIS) through invasive cancer, MMTV-HER2-driven tumors and also HER2+ human cancer cell lines are exquisitely sensitive to this novel PERK inhibitor. We found that early MMTV-HER2+ lesions require PERK for HER2-driven alterations in ductal epithelial organization, and that LY4 impairs the expansion of established HER2+ tumor cells in 3D organotypic cultures and in vivo. Importantly, PERK inhibition blunted metastasis development. This effect was linked to the ability of the PERK inhibitor to eradicate solitary HER2+ disseminated tumor cells that, in their majority, are dormant or slow-cycling, but that represent the seeds for further metastases. Mechanism analyses revealed that PERK inhibition indirectly blocked the phosphorylation of HER2 and EGFR and their downstream signaling activation in response to EGF, possibly by altering receptor protein quality control. Our data suggest that in HER2-driven cancers PERK inhibition might be a novel therapeutic strategy to treat primary and metastatic lesions. Citation Format: Veronica Calvo, Kirk A. Staschke, Maria Cristina Garcia Paredes, Alvaro Avivar-Valderas, Julie Cheung, Robert Wild, Alan C. Rigby, Eduardo F. Farias, Julio Aguirre-Ghiso. A PERK inhibitor that blocks HER2-driven tumorigenesis and suppresses metastasis by targeting single disseminated tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A38.