NXP800 Activates the Unfolded Protein Response, Altering AR and E2F Function to Impact Castration-Resistant Prostate Cancer Growth.
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Welti Jonathan, Bogdan Denisa, Figueiredo Ines, Coleman Ilsa, Jiménez Vacas Juan, Liodaki Kate, Weigl Franziska, Buroni Lorenzo, Zeng Wanting, Bernett Ilona, Bertan Claudia, Roumeliotis Theodoros I, Bhamra Amandeep, Rekowski Jan, Gurel Bora, Neeb Antje J, Ning Jian, Li Dapei, Gil Veronica S, Riisnaes Ruth, Miranda Susana, Crespo Mateus, Ferreira Ana, Tunariu Nina, Pasqua Elisa, Chessum Nicola, Cheeseman Matthew, Te Poele Robert, Powers Marissa, Carreira Suzanne, Choudhary Jyoti, Clarke Paul, Banerji Udai, Swain Amanda, Jones Keith, Yuan Wei, Workman Paul, Nelson Peter S, de Bono Johann S, Sharp Adam
Аннотация
EXPERIMENTAL DESIGN: We first did transcriptome analysis on multiple castration-resistant prostate cancer (CRPC) cohorts to correlate the association between the Gene Ontology cellular response to heat gene expression signature and overall survival. Next, we analyzed the impact of targeting the heat shock factor 1 (HSF1) pathway, with an inhibitor in clinical development, namely, NXP800 (formerly CCT361814), in models of treatment-resistant prostate cancer. Finally, we confirmed our mechanistic and phenotypic findings using an NXP800-resistant model and an in vivo model of CRPC.
RESULTS: We report that in multiple CRPC transcriptome cohorts, the Gene Ontology cellular response to heat gene expression signature associates with AR signaling and worse clinical outcome. We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely, NXP800, in prostate cancer. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant prostate cancer models.
CONCLUSIONS: Overall, NXP800 has antitumor activity against treatment-resistant prostate cancer models, including molecular subtypes with limited treatment options, supporting its consideration for prostate cancer-specific clinical development.