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

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

doi:10.3389/fonc.2023.1025443

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

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

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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 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.

Original language	English (US)
Article number	1025443
Journal	Frontiers in Oncology
Volume	13
DOIs	https://doi.org/10.3389/fonc.2023.1025443
State	Published - 2023

Keywords

LKB1
glucocorticoid
lung cancer
nuclear receptor
targeted therapy

ASJC Scopus subject areas

Oncology
Cancer Research

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10.3389/fonc.2023.1025443

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Huffman, K. E., Li, L. S., Carstens, R., Park, H., Girard, L., Avila, K., Wei, S., Kollipara, R., Timmons, B., Sudderth, J., Bendris, N., Kim, J., Villalobos, P., Fujimoto, J., Schmid, S., Deberardinis, R. J., Wistuba, I., Heymach, J., Kittler, R., ... Minna, J. D. (2023). Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers. Frontiers in Oncology, 13, Article 1025443. https://doi.org/10.3389/fonc.2023.1025443

Huffman, KE, Li, LS, Carstens, R, Park, H, Girard, L, Avila, K, Wei, S, Kollipara, R, Timmons, B, Sudderth, J, Bendris, N, Kim, J, Villalobos, P, Fujimoto, J, Schmid, S, Deberardinis, RJ, Wistuba, I, Heymach, J, Kittler, R , Akbay, EA , Posner, B, Wang, Y, Lam, S, Kliewer, SA , Mangelsdorf, DJ & Minna, JD 2023, 'Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers', Frontiers in Oncology, vol. 13, 1025443. https://doi.org/10.3389/fonc.2023.1025443

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title = "Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers",

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 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.",

keywords = "LKB1, glucocorticoid, lung cancer, nuclear receptor, targeted therapy",

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

note = "Publisher Copyright: Copyright {\textcopyright} 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.",

year = "2023",

doi = "10.3389/fonc.2023.1025443",

language = "English (US)",

volume = "13",

journal = "Frontiers in Oncology",

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T1 - Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers

AU - Huffman, Kenneth E.

AU - Li, Long Shan

AU - Carstens, Ryan

AU - Park, Hyunsil

AU - Girard, Luc

AU - Avila, Kimberley

AU - Wei, Shuguang

AU - Kollipara, Rahul

AU - Timmons, Brenda

AU - Sudderth, Jessica

AU - Bendris, Nawal

AU - Kim, Jiyeon

AU - Villalobos, Pamela

AU - Fujimoto, Junya

AU - Schmid, Sandra

AU - Deberardinis, Ralph J.

AU - Wistuba, Ignacio

AU - Heymach, John

AU - Kittler, Ralf

AU - Akbay, Esra A.

AU - Posner, Bruce

AU - Wang, Yuzhuo

AU - Lam, Stephen

AU - Kliewer, Steven A.

AU - Mangelsdorf, David J.

AU - Minna, John D.

N1 - Publisher Copyright: 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.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - LKB1

KW - glucocorticoid

KW - lung cancer

KW - nuclear receptor

KW - targeted therapy

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AN - SCOPUS:85152531059

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JO - Frontiers in Oncology

JF - Frontiers in Oncology

M1 - 1025443

ER -

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

Abstract

Keywords

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