Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergeticsmitochondrial priming

Praveena S. Thiagarajan, Xiaoliang Wu, Wei Zhang, Ivy Shi, Rakesh Bagai, Patrick Leahy, Yan Feng, Martina Veigl, Daniel Lindner, David Danielpour, Lihong Yin, Rafael Rosell, Trever G. Bivona, Zhenfeng Zhang, Patrick Chi-Chung Ma

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Abstract

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 drugescape emergence using EGFR precision inhibitor combined with broad BH3-mimetic to interrupt BCL-2/BCL-xL together, but not BCL-2 alone.

Original languageEnglish (US)
Pages (from-to)82013-82027
Number of pages15
JournalOncotarget
Volume7
Issue number50
DOIs
StatePublished - Jan 1 2016

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Metabolomics
Pharmaceutical Preparations
Energy Metabolism
Therapeutics
Neoplasms
Glutamine
Stem Cells
Lung

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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 Chi-Chung. / Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergeticsmitochondrial priming. In: Oncotarget. 2016 ; Vol. 7, No. 50. pp. 82013-82027.
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abstract = "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 drugescape 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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Thiagarajan, PS, Wu, X, Zhang, W, Shi, I, Bagai, R, Leahy, P, Feng, Y, Veigl, M, Lindner, D, Danielpour, D, Yin, L, Rosell, R, Bivona, TG, Zhang, Z & Ma, PC-C 2016, 'Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergeticsmitochondrial priming', Oncotarget, vol. 7, no. 50, pp. 82013-82027. https://doi.org/10.18632/oncotarget.13307

Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergeticsmitochondrial 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 Chi-Chung.

In: Oncotarget, Vol. 7, No. 50, 01.01.2016, p. 82013-82027.

Research output: Contribution to journalArticle

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