AUTHOR=Huffman Kenneth E. , Li Long Shan , Carstens Ryan , Park Hyunsil , Girard Luc , Avila Kimberley , Wei Shuguang , Kollipara Rahul , Timmons Brenda , Sudderth Jessica , Bendris Nawal , Kim Jiyeon , Villalobos Pamela , Fujimoto Junya , Schmid Sandra , Deberardinis Ralph J. , Wistuba Ignacio , Heymach John , Kittler Ralf , Akbay Esra A. , Posner Bruce , Wang Yuzhuo , Lam Stephen , Kliewer Steven A. , Mangelsdorf David J. , Minna John D. 

TITLE=Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers

JOURNAL=Frontiers in Oncology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1025443

DOI=10.3389/fonc.2023.1025443

ISSN=2234-943X

ABSTRACT=The glucocorticoid receptor (GR) is an important anti-cancer target in lymphoid cancers but has been understudied in solid tumors like lung cancer, although glucocorticoids are often given with chemotherapy regimens to mitigate side effects.  Here, we identify a GR mediated anti-cancer response in a subset of aggressive non-small cell lung cancers (NSCLCs) that harbor STK11/LKB1 mutations. Subcutaneous, orthotopic and metastatic NSCLC xenografts, biomarker-selected patient derived xenografts, and genetically engineered mouse models with KRAS/LKB1 mutant lung adenocarcinomas all showed marked anti-tumor responses with the glucocorticoid dexamethasone as a single agent or in combination with cisplatin. Mechanistically, GR activation triggers G1/S cell cycle arrest in LKB1 mutant NSCLCs by inducing the expression of the cyclin-dependent kinase inhibitor, p57(Kip2).  GR mediated cell cycle arrest did not interfere with radiotherapy response in vitro or with platinum response in vivo and shows evidence of apoptotic activation in a NSCLC patient derived xenograft (PDX) STK11/LKB1 mutant model. These findings identify a previously unknown GR mediated therapeutic vulnerability in STK11/LKB1 mutant NSCLCs.