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

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 dexamethasone-GR mediated anti-cancer...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10078807/
https://www.ncbi.nlm.nih.gov/pubmed/37035141
http://dx.doi.org/10.3389/fonc.2023.1025443
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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.
author_facet 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.
author_sort Huffman, Kenneth E.
collection PubMed
description 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 dexamethasone-GR mediated anti-cancer response in a subset of aggressive non-small cell lung cancers (NSCLCs) that harbor Serine/Threonine Kinase 11 (STK11/LKB1) mutations. High tumor expression of carbamoyl phosphate synthase 1 (CPS1) was strongly linked to the presence of LKB1 mutations, was the best predictor of NSCLC dexamethasone (DEX) sensitivity (p < 10(-16)) but was not mechanistically involved in DEX sensitivity. Subcutaneous, orthotopic and metastatic NSCLC xenografts, biomarker-selected, STK11/LKB1 mutant patient derived xenografts, and genetically engineered mouse models with KRAS/LKB1 mutant lung adenocarcinomas all showed marked in vivo 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, CDKN1C/p57(Kip2). All findings were confirmed with functional genomic experiments including CRISPR knockouts and exogenous expression. Importantly, DEX-GR mediated cell cycle arrest did not interfere with NSCLC radiotherapy, or platinum response in vitro or with platinum response in vivo. While DEX induced LKB1 mutant NSCLCs in vitro exhibit markers of cellular senescence and demonstrate impaired migration, in vivo DEX treatment of a patient derived xenograft (PDX) STK11/LKB1 mutant model resulted in expression of apoptosis markers. These findings identify a previously unknown GR mediated therapeutic vulnerability in STK11/LKB1 mutant NSCLCs caused by induction of p57(Kip2) expression with both STK11 mutation and high expression of CPS1 as precision medicine biomarkers of this vulnerability.
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spelling pubmed-100788072023-04-07 Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers 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. Front Oncol Oncology 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 dexamethasone-GR mediated anti-cancer response in a subset of aggressive non-small cell lung cancers (NSCLCs) that harbor Serine/Threonine Kinase 11 (STK11/LKB1) mutations. High tumor expression of carbamoyl phosphate synthase 1 (CPS1) was strongly linked to the presence of LKB1 mutations, was the best predictor of NSCLC dexamethasone (DEX) sensitivity (p < 10(-16)) but was not mechanistically involved in DEX sensitivity. Subcutaneous, orthotopic and metastatic NSCLC xenografts, biomarker-selected, STK11/LKB1 mutant patient derived xenografts, and genetically engineered mouse models with KRAS/LKB1 mutant lung adenocarcinomas all showed marked in vivo 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, CDKN1C/p57(Kip2). All findings were confirmed with functional genomic experiments including CRISPR knockouts and exogenous expression. Importantly, DEX-GR mediated cell cycle arrest did not interfere with NSCLC radiotherapy, or platinum response in vitro or with platinum response in vivo. While DEX induced LKB1 mutant NSCLCs in vitro exhibit markers of cellular senescence and demonstrate impaired migration, in vivo DEX treatment of a patient derived xenograft (PDX) STK11/LKB1 mutant model resulted in expression of apoptosis markers. These findings identify a previously unknown GR mediated therapeutic vulnerability in STK11/LKB1 mutant NSCLCs caused by induction of p57(Kip2) expression with both STK11 mutation and high expression of CPS1 as precision medicine biomarkers of this vulnerability. Frontiers Media S.A. 2023-03-23 /pmc/articles/PMC10078807/ /pubmed/37035141 http://dx.doi.org/10.3389/fonc.2023.1025443 Text en Copyright © 2023 Huffman, Li, Carstens, Park, Girard, Avila, Wei, Kollipara, Timmons, Sudderth, Bendris, Kim, Villalobos, Fujimoto, Schmid, Deberardinis, Wistuba, Heymach, Kittler, Akbay, Posner, Wang, Lam, Kliewer, Mangelsdorf and Minna https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
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.
Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers
title Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers
title_full Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers
title_fullStr Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers
title_full_unstemmed Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers
title_short Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers
title_sort glucocorticoid mediated inhibition of lkb1 mutant non-small cell lung cancers
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10078807/
https://www.ncbi.nlm.nih.gov/pubmed/37035141
http://dx.doi.org/10.3389/fonc.2023.1025443
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