@article{1a7d53cdf25c46dc949925b6c78c0043,
title = "Inhibition of Karyopherin b1-Mediated Nuclear Import Disrupts Oncogenic Lineage-Defining Transcription Factor Activity in Small Cell Lung Cancer",
abstract = "Genomic studies support the classification of small cell lung cancer (SCLC) into subtypes based on the expression of lineage-defining transcription factors ASCL1 and NEUROD1, which together are expressed in ̴86% of SCLC. ASCL1 and NEUROD1 activate SCLC oncogene expression, drive distinct transcriptional programs, and maintain the in vitro growth and oncogenic properties of ASCL1 or NEUROD1-expressing SCLC. ASCL1 is also required for tumor formation in SCLC mouse models. A strategy to inhibit the activity of these oncogenic drivers may therefore provide both a targeted therapy for the predominant SCLC subtypes and a tool to investigate the underlying lineage plasticity of established SCLC tumors. However, there are no known agents that inhibit ASCL1 or NEUROD1 function. In this study, we identify a novel strategy to pharmacologically target ASCL1 and NEUROD1 activity in SCLC by exploiting the nuclear localization required for the function of these transcription factors. Karyopherin b1 (KPNB1) was identified as a nuclear import receptor for both ASCL1 and NEUROD1 in SCLC, and inhibition of KPNB1 led to impaired ASCL1 and NEUROD1 nuclear accumulation and transcriptional activity. Pharmacologic targeting of KPNB1 preferentially disrupted the growth of ASCL1{\th} and NEUROD1{\th} SCLC cells in vitro and suppressed ASCL1{\th} tumor growth in vivo, an effect mediated by a combination of impaired ASCL1 downstream target expression, cell-cycle activity, and proteostasis. These findings broaden the support for targeting nuclear transport as an anticancer therapeutic strategy and have implications for targeting lineage-transcription factors in tumors beyond SCLC.(Figure",
author = "Kelenis, {Demetra P.} and Rodarte, {Kathia E.} and Kollipara, {Rahul K.} and Karine Pozo and Choudhuri, {Shreoshi Pal} and Spainhower, {Kyle B.} and Wait, {Sarah J.} and Victor Stastny and Oliver, {Trudy G.} and Johnson, {Jane E.}",
note = "Funding Information: K. Pozo reports grants from NCI P50CA70907 during the conduct of the study and other support from Immatics US outside the submitted work. T.G. Oliver reports grants from NIH during the conduct of the study; in addition, T.G. Oliver has a patent for US11124841B2 issued to the University of Utah Research Foundation. J.E. Johnson reports grants from NCI during the conduct of the study. No disclosures were reported by the other authors. Funding Information: nuclear import expertise of Dr. Yuh Min Chook. They thank Chaoying Liang (UTSW Microarray Core) for next-generation sequencing, Noelle Williams (Preclinical Pharmacology Core) for mouse pharmacokinetic analysis and assistance with compound formulation for in vivo delivery, and Terry Shih (Flow Cytometry Core) for outstanding technical advice and service. The authors also thank Trisha Savage for help with PDX implantation, John Minna, Luc Girard, Boning Gao, and Adi Gazdar (deceased) for their work on SCLC cell lines and lineage-defining TFs, and Charles Rudin and J.T. Poirier for providing SCLC PDXs. Funding for this project was provided by NCI F30 CA228314 to D.P. Kelenis, NCI U01CA213338 supporting J.E. Johnson, a Career Development Award (NCI Spore Grant in Lung Cancer P50CA70907) to K. Pozo, CPRIT Training Grant RP160157 to K.E. Rodarte, NCI U24CA213274 supporting V. Stastny, NCI U01CA231844 and U24CA213274 supporting T.G. Oliver, and P30CA042014 to Huntsman Cancer Institute. Publisher Copyright: {\textcopyright}2022 American Association for Cancer Research.",
year = "2022",
month = sep,
day = "1",
doi = "10.1158/0008-5472.CAN-21-3713",
language = "English (US)",
volume = "82",
pages = "3058--3073",
journal = "Cancer research",
issn = "0008-5472",
number = "17",
}