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LKB1 Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT

INTRODUCTION: Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer, and understanding the pathways and phenotypes altered as a consequence will aid the development of targeted therapeutic strategies. Gene and protein expressions in a murine model of v-Ki-ras2 Kirsten r...

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Autores principales: Kaufman, Jacob M., Amann, Joseph M., Park, Kyungho, Arasada, Rajeswara Rao, Li, Haotian, Shyr, Yu, Carbone, David P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026179/
https://www.ncbi.nlm.nih.gov/pubmed/24828662
http://dx.doi.org/10.1097/JTO.0000000000000173
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author Kaufman, Jacob M.
Amann, Joseph M.
Park, Kyungho
Arasada, Rajeswara Rao
Li, Haotian
Shyr, Yu
Carbone, David P.
author_facet Kaufman, Jacob M.
Amann, Joseph M.
Park, Kyungho
Arasada, Rajeswara Rao
Li, Haotian
Shyr, Yu
Carbone, David P.
author_sort Kaufman, Jacob M.
collection PubMed
description INTRODUCTION: Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer, and understanding the pathways and phenotypes altered as a consequence will aid the development of targeted therapeutic strategies. Gene and protein expressions in a murine model of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (Kras)-mutant lung cancer have been studied to gain insight into the biology of these tumors. However, the molecular consequences of LKB1 loss in human lung cancer have not been fully characterized. METHODS: We studied gene expression profiles associated with LKB1 loss in resected lung adenocarcinomas, non–small-cell lung cancer cell lines, and murine tumors. The biological significance of dysregulated genes was interpreted using gene set enrichment and transcription factor analyses and also by integration with somatic mutations and proteomic data. RESULTS: Loss of LKB1 is associated with consistent gene expression changes in resected human lung cancers and cell lines that differ substantially from the mouse model. Our analysis implicates novel biological features associated with LKB1 loss, including altered mitochondrial metabolism, activation of the nuclear respiratory factor 2 (NRF2) transcription factor by kelch-like ECH-associated protein 1 (KEAP1) mutations, and attenuation of the phosphatidylinositiol 3-kinase and v-akt murine thymoma viral oncogene homolog (PI3K/AKT) pathway. Furthermore, we derived a 16-gene classifier that accurately predicts LKB1 mutations and loss by nonmutational mechanisms. In vitro, transduction of LKB1 into LKB1-mutant cell lines results in attenuation of this signature. CONCLUSION: Loss of LKB1 defines a subset of lung adenocarcinomas associated with characteristic molecular phenotypes and distinctive gene expression features. Studying these effects may improve our understanding of the biology of these tumors and lead to the identification of targeted treatment strategies.
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spelling pubmed-40261792014-08-14 LKB1 Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT Kaufman, Jacob M. Amann, Joseph M. Park, Kyungho Arasada, Rajeswara Rao Li, Haotian Shyr, Yu Carbone, David P. J Thorac Oncol Original Articles INTRODUCTION: Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer, and understanding the pathways and phenotypes altered as a consequence will aid the development of targeted therapeutic strategies. Gene and protein expressions in a murine model of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (Kras)-mutant lung cancer have been studied to gain insight into the biology of these tumors. However, the molecular consequences of LKB1 loss in human lung cancer have not been fully characterized. METHODS: We studied gene expression profiles associated with LKB1 loss in resected lung adenocarcinomas, non–small-cell lung cancer cell lines, and murine tumors. The biological significance of dysregulated genes was interpreted using gene set enrichment and transcription factor analyses and also by integration with somatic mutations and proteomic data. RESULTS: Loss of LKB1 is associated with consistent gene expression changes in resected human lung cancers and cell lines that differ substantially from the mouse model. Our analysis implicates novel biological features associated with LKB1 loss, including altered mitochondrial metabolism, activation of the nuclear respiratory factor 2 (NRF2) transcription factor by kelch-like ECH-associated protein 1 (KEAP1) mutations, and attenuation of the phosphatidylinositiol 3-kinase and v-akt murine thymoma viral oncogene homolog (PI3K/AKT) pathway. Furthermore, we derived a 16-gene classifier that accurately predicts LKB1 mutations and loss by nonmutational mechanisms. In vitro, transduction of LKB1 into LKB1-mutant cell lines results in attenuation of this signature. CONCLUSION: Loss of LKB1 defines a subset of lung adenocarcinomas associated with characteristic molecular phenotypes and distinctive gene expression features. Studying these effects may improve our understanding of the biology of these tumors and lead to the identification of targeted treatment strategies. Lippincott Williams & Wilkins 2014-06 2014-05-30 /pmc/articles/PMC4026179/ /pubmed/24828662 http://dx.doi.org/10.1097/JTO.0000000000000173 Text en Copyright © 2014 by the International Association for the Study of Lung Cancer This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
spellingShingle Original Articles
Kaufman, Jacob M.
Amann, Joseph M.
Park, Kyungho
Arasada, Rajeswara Rao
Li, Haotian
Shyr, Yu
Carbone, David P.
LKB1 Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT
title LKB1 Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT
title_full LKB1 Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT
title_fullStr LKB1 Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT
title_full_unstemmed LKB1 Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT
title_short LKB1 Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT
title_sort lkb1 loss induces characteristic patterns of gene expression in human tumors associated with nrf2 activation and attenuation of pi3k-akt
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026179/
https://www.ncbi.nlm.nih.gov/pubmed/24828662
http://dx.doi.org/10.1097/JTO.0000000000000173
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