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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
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.
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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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