@article{2a5c1a868d1649bd95a07307a9fc398a,
title = "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.",
author = "Su Deng and Choushi Wang and Yunguan Wang and Yaru Xu and Xiaoling Li and Johnson, {Nickolas A.} and Atreyi Mukherji and Lo, {U. Ging} and Lingfan Xu and Julisa Gonzalez and Metang, {Lauren A.} and Jianfeng Ye and Tirado, {Carla Rodriguez} and Kathia Rodarte and Yinglu Zhou and Zhiqun Xie and Carlos Arana and Valli Annamalai and Xihui Liu and {Vander Griend}, {Donald J.} and Douglas Strand and Hsieh, {Jer Tsong} and Bo Li and Ganesh Raj and Tao Wang and Ping Mu",
note = "Funding Information: G.R. holds issued and pending patents, which have been licensed to EtiraRx. G.R. serves or has served in an advisory role to Bayer, Johnson and Johnson, Myovant, EtiraRx, Amgen, Pfizer and Astellas. G.R. has or has had grant support from Bayer, EtiraRx and Johnson and Johnson. All other authors declare that they have no competing interests. Funding Information: We thank C.L. Sawyers at MSKCC for providing the parental LNCaP/AR and CWR22Pc cell lines. We thank Y. Chen and C. Lee at MSKCC for providing the human organoid models. We thank K. O{\textquoteright}Donnell, M. Buszczak and J. Wu at UT Southwestern Medical Center for helpful discussion. This work was supported, or partially supported, by the National Cancer Institute/National Institutes of Health (5R00CA218885 and 1R37CA258730 to P.M., 1P30CA142543 and 1R01CA258584 to T.W., 1R01CA245318 to B.L., R01CA178431 to D.J.V.G. and T32C124334 to C.R.T.), the Department of Defense (W81XWH-18-1-0411 and W81XWH21-1-0520 to P.M., W81XWH-16-1-0474 to J.-T.H. and W81XWH2110418 to X. Li), the Cancer Prevention Research Institute (RR170050 and RP220473 to P.M., RP190208 to T.W., RR170079 to B.L. and RP160157 to K.R.), the Prostate Cancer Foundation (17YOUN12 to P.M.), the Welch Foundation (I-2005-20190330 to P.M.), the UTSW Deborah and W.A. Tex Moncrief, Jr., Scholar in Medical Research Award (P.M.), the UTSW Harold C. Simmons Cancer Center Pilot Award (P.M.) and the UTSW CCSG Data Science Shared Resources (D.S. and T.W.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = sep,
doi = "10.1038/s43018-022-00431-9",
language = "English (US)",
volume = "3",
pages = "1071--1087",
journal = "Nature Cancer",
issn = "2662-1347",
publisher = "Nature Research",
number = "9",
}