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Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming
The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a n...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347670/ https://www.ncbi.nlm.nih.gov/pubmed/27852038 http://dx.doi.org/10.18632/oncotarget.13307 |
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author | Thiagarajan, Praveena S. Wu, Xiaoliang Zhang, Wei Shi, Ivy Bagai, Rakesh Leahy, Patrick Feng, Yan Veigl, Martina Lindner, Daniel Danielpour, David Yin, Lihong Rosell, Rafael Bivona, Trever G. Zhang, Zhenfeng Ma, Patrick C. |
author_facet | Thiagarajan, Praveena S. Wu, Xiaoliang Zhang, Wei Shi, Ivy Bagai, Rakesh Leahy, Patrick Feng, Yan Veigl, Martina Lindner, Daniel Danielpour, David Yin, Lihong Rosell, Rafael Bivona, Trever G. Zhang, Zhenfeng Ma, Patrick C. |
author_sort | Thiagarajan, Praveena S. |
collection | PubMed |
description | The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGFβ2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming. Cells undergoing early adaptive drug escape are in proliferative-metabolic quiescent, with enhanced EMT-ness and stem cell signaling, exhibiting global bioenergetics suppression including reverse Warburg, and are susceptible to glutamine deprivation and TGFβ2 inhibition. Our study further supports a preemptive therapeutic targeting of bioenergetics and mitochondrial priming to impact early drug-escape emergence using EGFR precision inhibitor combined with broad BH3-mimetic to interrupt BCL-2/BCL-xL together, but not BCL-2 alone. |
format | Online Article Text |
id | pubmed-5347670 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53476702017-03-31 Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming Thiagarajan, Praveena S. Wu, Xiaoliang Zhang, Wei Shi, Ivy Bagai, Rakesh Leahy, Patrick Feng, Yan Veigl, Martina Lindner, Daniel Danielpour, David Yin, Lihong Rosell, Rafael Bivona, Trever G. Zhang, Zhenfeng Ma, Patrick C. Oncotarget Priority Research Paper The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGFβ2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming. Cells undergoing early adaptive drug escape are in proliferative-metabolic quiescent, with enhanced EMT-ness and stem cell signaling, exhibiting global bioenergetics suppression including reverse Warburg, and are susceptible to glutamine deprivation and TGFβ2 inhibition. Our study further supports a preemptive therapeutic targeting of bioenergetics and mitochondrial priming to impact early drug-escape emergence using EGFR precision inhibitor combined with broad BH3-mimetic to interrupt BCL-2/BCL-xL together, but not BCL-2 alone. Impact Journals LLC 2016-11-11 /pmc/articles/PMC5347670/ /pubmed/27852038 http://dx.doi.org/10.18632/oncotarget.13307 Text en Copyright: © 2016 Thiagarajan et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Priority Research Paper Thiagarajan, Praveena S. Wu, Xiaoliang Zhang, Wei Shi, Ivy Bagai, Rakesh Leahy, Patrick Feng, Yan Veigl, Martina Lindner, Daniel Danielpour, David Yin, Lihong Rosell, Rafael Bivona, Trever G. Zhang, Zhenfeng Ma, Patrick C. Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming |
title | Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming |
title_full | Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming |
title_fullStr | Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming |
title_full_unstemmed | Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming |
title_short | Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming |
title_sort | transcriptomic-metabolomic reprogramming in egfr-mutant nsclc early adaptive drug escape linking tgfβ2-bioenergetics-mitochondrial priming |
topic | Priority Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347670/ https://www.ncbi.nlm.nih.gov/pubmed/27852038 http://dx.doi.org/10.18632/oncotarget.13307 |
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