JAK-STAT Signaling Enables Lineage Plasticity-driven AR Targeted Therapy Resistance

Deng, S.; Wang, C.; Wang, Y.; Xu, Y.; Li, X.; Johnson, N.; Lo, U.-G.; Xu, L.; Gonzalez, J.; Metang, L.; Ye, J.; Tirado, C. R.; Rodarte, K.; Xie, Z.; Arana, C.; Annamalai, V.; Hsieh, J.-T.; Griend, D. V.; Li, B.; Wang, T.; Mu, P.

doi:10.1101/2021.11.02.466956

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bioRxiv · 10.1101/2021.11.02.466956

JAK-STAT Signaling Enables Lineage Plasticity-driven AR Targeted Therapy Resistance

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Abstract

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity-driven resistance, the molecular mechanisms of acquiring lineage plasticity have not been fully elucidated. Through integrated transcriptomic and single cell RNA-Seq (scRNA-Seq) analysis of more than 80,000 cells, we reveal for the first time that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven AR targeted therapy resistance in prostate cancer. Ectopic activation of JAK-STAT signaling is specifically required for the AR targeted therapy resistance of subclones expressing multilineage, stem-like and epithelial-to-mesenchymal transition (EMT) lineage transcriptional programs and represents a potential therapeutic target for overcoming AR targeted therapy resistance. One-Sentence SummaryJAK-STAT signaling is a crucial executor in promoting lineage plasticity-driven AR therapy resistance in prostate cancer.

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Deng, S., Wang, C., Wang, Y., Xu, Y., Li, X., Johnson, N., Lo, U.-G., Xu, L., Gonzalez, J., Metang, L., Ye, J., Tirado, C. R., Rodarte, K., Xie, Z., Arana, C., Annamalai, V., Hsieh, J.-T., Griend, D. V., Li, B., Wang, T., Mu, P.. 2021-11-02. JAK-STAT Signaling Enables Lineage Plasticity-driven AR Targeted Therapy Resistance. https://doi.org/10.1101/2021.11.02.466956

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