Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance
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, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK–STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK–STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK–STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 05, 2022
- Source ID
- 10.1038/s43018-022-00431-9
Entities
People
- Atreyi Mukherji
- Bo Li
- Carla Rodriguez Tirado
- Carlos Arana
- Choushi Wang
- Donald J Vander Griend
- Douglas W. Strand
- Ganesh V Raj
- Jer-Tsong Hsieh
- Jianfeng Ye
- Julisa Gonzalez
- Kathia Rodarte
- Lauren A. Metang
- Lingfan Xu
- Nickolas A. Johnson
- Ping Mu
- Su Deng
- Tao Wang
- U-ging Lo
- Valli Annamalai
- Xiaoling Li
- Xihui Liu
- Yaru Xu
- Yinglu Zhou
- Yunguan Wang
- Zhiqun Xie
Organizations
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute
- Prostate Cancer Foundation
- Robert A. Welch Foundation
- United States Department of Defense
- University of Texas Southwestern Medical Center